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CHRONIC MYELOPROLIFERATIVE

NEOPLASMS

M. Kazmierczak 2016

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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. Relative erythrocytosis (pseudopolycythemia):

1. Hemoconcentration

2. Spurious polycythemia (Gaisboek syndrome)

II. Absolute erythrocytosis (Polycythemia):

A. Primery erythrocytosis

1. Polycythemia vera

2. Familial erythrocytosis

B. Secondary erythrocytosis (abnormal increase of serum erythropoietin level)

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ERYTHROCYTOSIS (Classification)

(2)

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”

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

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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 bleeding

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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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 picture1. 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

MPN symptoms by subtype

Geyer HL, et al. Hematology 2014;277

World Health Organization Diagnostic Criteria for Polycythemia Vera,

Essential Thrombocythemia and Primary Myelofibrosis

Abbreviations: BM, bone marrow; CML, chronic myelogenous leukemia; EEC, endogenous erythroid colony; Epo, erythropoietin; Hct, hematocrit; Hgb, hemoglobin;

LDH, lactate dehydrogenase; MDS, myelodysplastic syndromes; PMF, primary myelofibrosis; PV, polycythemia vera; WHO, World Health Organization.

a PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and second minor criteria. ET diagnosis requires

meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.

b or Hgb or Hct > 99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above mean normal predicted or Hgb >17

g/dL (men)/>15 g/dL (women) if associated with a sustained increase of 2 g/dL from baseline that cannot be attributed to correction of iron deficiency.

c Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.

d or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and

often decreased erythropoiesis (i.e. pre-fibrotic PMF).

Tefferi A. Am. J. Hematol. 2015;90:163–173

MPN complication rates, prognosis and risk

scoring algorithms

Geyer HL, et al. Hematology 2014;277

Practical Algorithm for Diagnosis

of Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF)

Tefferi A, Barbui T. Am J Hematol. 2015 Apr 14. doi: 10.1002/ajh.24037. [Epub ahead of print

Aspirin is used in the absence of treatment contraindications including clinically significant acquired von Willebrand syndrome. We recommend performing

ristocetin cofactor activity in patients with over 1 million platelets per microliter and holding aspirin if the activity level is below 20%.

Contemporary treatment algorithm in essential

thrombocytopenia and polycythaemia vera

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POLYCYTHEMIA VERA

Phlebotomy

- 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%

- fluid replacement so that the patients remains isovolemic

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.

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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.

Practical Algorithm for Diagnosis

of Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF)

World Health Organization Diagnostic Criteria for Polycythemia Vera,

Essential Thrombocythemia and Primary Myelofibrosis

Abbreviations: BM, bone marrow; CML, chronic myelogenous leukemia; EEC, endogenous erythroid colony; Epo, erythropoietin; Hct, hematocrit; Hgb, hemoglobin;

LDH, lactate dehydrogenase; MDS, myelodysplastic syndromes; PMF, primary myelofibrosis; PV, polycythemia vera; WHO, World Health Organization.

a PV diagnosis requires meeting either both major criteria and one minor criterion or the first major criterion and second minor criteria. ET diagnosis requires

meeting all four major criteria. PMF diagnosis requires meeting all three major criteria and two minor criteria.

b or Hgb or Hct > 99th percentile of reference range for age, sex, or altitude of residence or red cell mass >25% above mean normal predicted or Hgb >17

g/dL (men)/>15 g/dL (women) if associated with a sustained increase of 2 g/dL from baseline that cannot be attributed to correction of iron deficiency.

c Small to large megakaryocytes with aberrant nuclear/cytoplasmic ratio and hyperchromatic and irregularly folded nuclei and dense clustering.

d or In the absence of reticulin fibrosis, the megakaryocyte changes must be accompanied by increased marrow cellularity, granulocytic proliferation and

often decreased erythropoiesis (i.e. pre-fibrotic PMF).

Tefferi A. Am. J. Hematol. 2015;90:163–173

MPN complication rates, prognosis and risk

scoring algorithms

Geyer HL, et al. Hematology 2014;277

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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

Contemporary Treatment Algorithm for Primary Myelofibrosis

MYELOFIBROSIS - therapy (1)

Drug used for the control of leukocytosis, thrombocytosis:

hydroxyurea

Drugs used for treatment of splenomegaly and constitutional symptoms:

hydroxyurea, ruxolitinib.

Drugs used for treatment of anemia include:

androgen preparations, prednisone, danazol, thalidomide, lenalidomide (in the

presence of del(5q).

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MYELOFIBROSIS - therapy (2)

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 10%).

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.

Supportive care: Allopurinol-to prevent hyperuricaemia.

Transfusions of packed red cells for anemia or platelets for

thrombocytopenia with bleeding

MYELOFIBROSIS - therapy (3)

Clinical trials:

- potentially disease-modifying agents such as inhibitors of mutated isocitrate

dehydrogenase protein and telomerase,

- immune conjugates directed at leukemic stem cells,

- another Janus kinase (JAK) inhibitor (momelotinib) - currently in a phase-3 study, in

improving anemia, in addition to its demonstrated efficacy in controlling splenomegaly and constitutional

symptoms.