CHRONIC MYELOPROLIFERATIVE
NEOPLASMS
1
M. Kazmierczak 11/2012
CHRONIC MYELOPROLIFERATIVE
NEOPLASMS (MPN)
1. Polycythemia vera
2. Chronic myeloid leukaemia
3. Essential thrombocythemia
4. Idiopathic myelofibrosis
5.Chronic neutrophilic leukemia
6. Chronic eosinophilic leukemia/hypereosinophilic
syndrome
2
CHRONIC MYELOPROLIFERATIVE
NEOPLASMS (MPN)
MPN 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.
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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”
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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)
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POLYCYTHEMIA VERA (PV)
Patogenesis
PV is a clonal disorder involving the hematopoietic stem cells; it leads to an
autonomous proliferation of the erythroid, myeloid, and megakaryocytic cell
lines. Increased erythroid proliferation is usually more prominent than that of the
other cell lines and occurs independently of erythropoietin levels (which are
usually very low in PV)
Epidemiology
The incidence rate of PV is approximately 2 per 100.000 population.
PV is slightly more prevalent in males with male/female ratio ranging from 1,2
to 2:1. Median age at diagnosis was 60 years in men and 62 years in women.
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POLYCYTHEMIA VERA
symptoms
1. Erythrocytosis and hyperviscosity, leading to impaired oxygen delivery:
• Poor CNS circulation: headaches, dizziness, vertigo, tinnitus and visual
disturbances
• Poor coronary circulation: angina pectoris
• Peripheral circulation intermittent claudication
2. Venous thrombosis or thromboembolism
3. Hemorrhage: epistaxis, gingival bleeding, ecchymoses, gastrointestinal bleedin
4. Abdominal pain secondary to peptic ulcer
5. Early satiety due to splenomegaly
6. Pruritus is secondary to increased histamine release from the basophils and
mast cells
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POLYCYTHEMIA VERA
physical examination
1. Splenomegaly – is present in 75% of patients at the time of
diagnosis.
2. Hepatomegaly - is present in approximately 30% of patients at
the time of diagnosis.
3. Hypertension
4. 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
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WHO criteria for polycythemia vera (2008)
Major criteria
1. Hemoglobin 18.5 g/dL in men, 16.5 g/dL in women or other
evidence of
increased red cell volume*
2. Presence of JAK2617VF or other functionally similar mutation
such as JAK2
exon 12 mutation
Minor criteria
1. Bone marrow biopsy showing hypercellularity for age with
trilineage growth
(panmyelosis) with prominent erythroid, granulocytic, and
megakaryocytic
proliferation
2. Serum erythropoietin level below the reference range for normal
3. Endogenous erythroid colony formation in vitro
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Diagnosis requires the presence of both major criteria
and 1minor criterion or the presence of the first major
criterion together with 2 minor criteria.
* Hemoglobin or hematocrit greater than 99th percentile of method-specific
reference range for age, sex, altitude of residence or hemoglobin greater
than 17 g/dL in men, 15 g/dL in women if associated with a documented
and sustained increase of at least 2 g/dL from an individual’s baseline
value that can not be attributed to correction of iron deficiency, or
elevated red cell mass greater than 25% above mean normal predicted
value
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Risk stratification in essential thrombocythemia and
polycythemia vera
Low risk
Age<60 yr,
No history of thrombosis,
Platelet count<1,0 milion/μL, and
No cardiovascular risk factors (smoking, obesity)
High risk
Age≥60 yr or
A previous history of thrombosis
Intermediate risk
Neither high risk nor low risk
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POLYCYTHEMIA VERA -therapy (1)
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 other day until the
hematocrit is less than 45% (M), 42% (F)
- older patients or these with underlying cardiovascular disase should
undergo smaller phlebotomies 200-300mL twice weekly or
100-150mL every day until Ht<45%
- 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
Aspirin 75mg/d unless contrindicated
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POLYCYTHEMIA VERA - therapy (2)
IV. Antiplatelets agents
• Aspirin initially 150-300mg/d,
maintence therapy 75-100 mg
• Ticlopidine 2x1
• Dipyridamol
• Anagrelide 2-2,5 mg/d
V. Other modalities
1. Radioactive phosphorus (in older than 75 years)
2. Busulfan – intermittent low dose (in older than 75 years)
3. Interferon alpha 3 million units 3 times weekly (<40 years)
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POLYCYTHEMIA VERA - supportive care
Severe itching (pruritus) — antihistamines, H2-receptor blockers, serotonin
reuptake inhibitors, interferon alpha, and in resistant cases, myelosuppression.
Hyperuricemia — allopurinol 300mg/day
Erythromelalgia (a burning pain in the feet or hands accompanied by erythema,
pallor or cyanosis) — low-dose aspirin (Grade 1C). Erythromelalgia
unresponsive to treatment with low-dose aspirin should be treated with
myelosuppression.
Bleeding — Extraneous causes for bleeding (eg, use of high-dose aspirin,
antiplatelet agents, anticoagulants) should be stopped. Patients should be
evaluated for acquired von Willebrand disease and treated accordingly.
POLYCYTHEMIA VERA -prognosis
• Untreated patients– the median survival ranges from 1-3 years
• Patients treated with phlebotomy or/and hydroxyurea
- median survival is 13,9 years
• Patients treated with 32P
- median survival is 11,8 years
The frequency of acute leukemia (%):
– Patients treated with phlebotomy 1,5 %
– Patients treated with 32P
9,6%
The frequency of myelofibrosis (%):
– Patients treated with phlebotomy 8,6 %
– Patients treated with 32P
7,7%
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Myelofibrosis=agnogenic myeloid metaplasia
(primary myelofibrosis, osteomyelofibrosis, idiopathic myelofibrosis,
myelofibrosis with myeloid metaplasia )
Myelofibrosis is a chronic myeloproliferative neoplasms 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.
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MYELOFIBROSIS
•
•
•
The incidence of Myelofibrosis is about 0,5/100.000. The median
age at diagnosis was approximately 65 years.
Common complaints: fatigue, weight loss, night sweats, bone pain,
abdominal pain, fever
Physical findings: splenomegaly (often huge), hepatomegaly (in
about 50% of patients), symptoms of anaemia and
thrombocytopenia
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MYELOFIBROSIS
- laboratory findings (1)
• Anemia - Hb<10g/dL in 60% of patients
• Leukocytosis with counts generally below 50G/L (in about 50%),
•
•
•
•
•
•
leukopenia
(in about 25% at the time of diagnosis)
thrombocytosis in 50% at the time of diagnosis, with disease progression
thrombocytopenia becomes common
eosinophilia and basophilia may be present
retikulocytosis
LAP score is usually elevaatedd
Increased level of lactate dehydrogenase
uric acid level is increased in most patients
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MYELOFIBROSIS
- laboratory findings(2)
• Peripheral blood smear: anisocytosis and poikilocytosis with the
presence of teardrop-shaped and nucleated red cells, immature
neutrophils but myeloblasts not always
• Aspiration of bone marrow is usually ansuccessful (dry tap).
Smears from successful aspirates usually show neutrophilic and
megakaryocytic hyperplasia
• Trephine biopsy often shows a hypercellular marrow with increased
reticulin fibers and variable collagen deposition . Increased numbers of
megakaryocytes are frequently seen.
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WHO criteria for primary myelofibrosis
(2008)
Major criteria
1. Presence of megakaryocyte proliferation and atypia,* usually
accompanied by either reticulin and/or collagen fibrosis, or, in the
absence of significant reticulin fibrosis, the megakaryocyte changes must
be accompanied by an increased bone marrow cellularity characterized
by granulocytic proliferation and often decreased erythropoiesis (ie,
prefibrotic cellular-phase disease)
2. Not meeting WHO criteria for PV,† CML,‡ MDS,§ or other myeloid
neoplasm
3. Demonstration of JAK2617VF or other clonal marker (eg,
MPL515WL/K), or in the absence of a clonal marker, no evidence of
bone marrow fibrosis due
to underlying inflammatory or other neoplastic diseases¶
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WHO criteria for primary myelofibrosis
(2008)
Minor criteria
1. Leukoerythroblastosis
2. Increase in serum lactate dehydrogenase level
3. Anemia
4. Palpable splenomegaly
Diagnosis requires meeting all 3 major criteria and 2
minor criteria.
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WHO criteria for primary myelofibrosis
(2008)
* Small to large megakaryocytes with an aberrant nuclear/cytoplasmic ratio and
hyperchromatic, bulbous, or irregularly folded nuclei and dense clustering.
† Requires the failure of iron replacement therapy to increase hemoglobin level to
the polycythemia vera range in the presence of decreased serum ferritin.
Exclusion of polycythemia vera is based on hemoglobin and hematocrit levels.
Red cell mass measurement is not required.
‡ Requires the absence of BCR-ABL.
§ Requires the absence of dyserythropoiesis and dysgranulopoiesis.
¶ Secondary to infection, autoimmune disorder or other chronic inflammatory
condition, hairy cell leukemia or other lymphoid neoplasm, metastatic
malignancy, or toxic (chronic) myelopathies. It should be noted that patients
with conditions associated with reactive myelofibrosis are not immune to
primary myelofibrosis and the diagnosis should be considered in such cases if
other criteria are met. Degree of abnormality could be borderline or marked.
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Dynamic IPSS :
·
·
·
·
·
Age >65 years: 1 point
Leukocyte count >25,000/microL: 1 point
Hemoglobin <10 g/dL: 2 points
Circulating blast cells ≥1 percent: 1 point
Presence of constitutional symptoms: 1 point
Subjects with zero, one to two, three to four, or 5 to 6 points were considered low,
intermediate-1, intermediate-2, or high risk, respectively.
DIPSS Plus — IPSS-independent prognostic factors for survival in PMF have been
identified, such as unfavorable karyotype (complex karyotype or sole or two abnormalities
that include +8, -7/7q-, i(17q), -5/5q-, 12p-, inv(3), or 11q23 rearrangements),
red cell transfusion need, and thrombocytopenia
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MYELOFIBROSIS - therapy (1)
1. Androgens(oxymetholone 2-4mg/kg) in anemia from decreased red
cell production -overall response is about 40%
2. Cortykosteroids(prednisone 1mg/kg) in anemia with shortened red
cell life-span-response in 25-50% of patients
3. Hydroxyurea (15- 20mg/kg) for the control of leukocytosis,
thrombocytosis, or organomegaly
4. Allopurinol-to prevent hyperuricaemia
5. Transfusions of packed red cells for anemia or platelets for
thrombocytopenia with bleeding
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MYELOFIBROSIS - therapy (2)
6. 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%).
7. Splenic irradiation: when there is a contrindication to
splenectomy
8. Allogeneic stem-cell transplantation: for young patients
who have a poor prognosis and have a suitable donor
identified.
9. Other: Interferon-, antifibrotic and antiangiogenic drugs
(anagrelide, suramin, pirfenidone, thalidomide, imatinib,
lenalidomide, JAK2 inhibitors (Ruxolitinib)
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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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ESSENTIAL THROMBOCYTHEMIA
(ET)
ET is a clonal myeloproliferative neoplasms
characterized by bone marrow hyperplasia
with excessive proliferation of megakaryocytes
and sustained elevation of the platelet count.
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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
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WHO criteria for essential
thrombocythemia (ET; 2008)
1. Sustained platelet count 450 109/L*
2. Bone marrow biopsy specimen showing proliferation mainly of the
megakaryocytic lineage with increased numbers of enlarged, mature
megakaryocytes; no significant increase or left-shift of neutrophil
granulopoiesis or erythropoiesis
3. Not meeting WHO criteria for PV,† PMF,‡ CML,§ MDS,¶ or other myeloid
neoplasm
4. Demonstration of JAK2617VF or other clonal marker, or in the
absence of a clonal marker, no evidence for reactive thrombocytosis
Diagnosis requires meeting all 4 criteria.
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WHO criteria for essential
thrombocythemia (ET; 2008)
* During the work-up period.
† Requires the failure of iron replacement therapy to increase hemoglobin level
to the PV range in the presence of decreased serum ferritin. Exclusion of PV is based
on hemoglobin and hematocrit levels, and red cell mass measurement is not
required.
‡ Requires the absence of relevant reticulin fibrosis, collagen fibrosis, peripheral
blood leukoerythroblastosis, or markedly hypercellular marrow for age accompanied
by megakaryocyte morphology that is typical for PMF small to large with an
aberrant nuclear/cytoplasmic ratio and hyperchromatic, bulbous or irregularly folded
nuclei and dense clustering.
§ Requires the absence of BCR-ABL.
¶ Requires absence of dyserythropoiesis and dysgranulopoiesis.
Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery,
infection, inflammation, connective tissue disease, metastatic cancer, and
Lymphoproliferative disorders. However, the presence of a condition associated with
reactive thrombocytosis does not exclude the possibility of ET if the first three criteria
are met.
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International Prognostic Score for
Essential thrombocythemia (IPSET):
- age ≥60: 2 points;
- white blood cell count ≥11,000/microL: 1 point;
- history of thrombosis: 1 point.
Median survivals were as follows:
Low risk (total score zero): not reached
Intermediate risk (total score 1 or 2): 24.5 years
High risk (total score 3 or 4): 13.8 years
Risk stratification in essential thrombocythemia
Low risk
Age<60 yr,
No history of thrombosis,
Platelet count<1,0 milion/μL, and
No cardiovascular risk factors (smoking, obesity)
High risk
Age≥60 yr or
A previous history of thrombosis
Intermediate risk
Neither high risk nor low risk
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ESSENTIAL THROMBOCYTHEMIA -therapy
Low risk: No treatment or low-dose aspirin (Grade 2C)
Intermediate risk: low-dose aspirin + no consensus on treatment
High risk: platelet-lowering agents (··Grade 1B). Current initial regimen of choice is
hydroxyurea in combination with low dose aspirin. High-risk pregnant patient with ET:
interferon (Grade 2C).
In the presence of vasomotor symptoms or general indications for aspirin use (eg,
presence of cardiovascular risk factors) and in the absence of acquired von Willebrand
disease (··Grade 2C): low-dose aspirin (eg, ≤100 mg/day PO)
Patients with ET should be advised to discontinue smoking and control obesity and other
cardiovascular risk factors, if present.
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