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Myeloproliferative Disorders John Santangelo Proliferative 1. To grow or produce by multiplication of parts, as in budding or cell division, or by procreation. (bring forth) 2. To increase in number or spread rapidly and often excessively. Myelo Bone Marrow MPD

Myeloproliferative Disorders 18th Oct 2010

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Page 1: Myeloproliferative Disorders 18th Oct 2010

Myeloproliferative DisordersJohn Santangelo

Proliferative1. To grow or produce by multiplication of parts, as in budding or cell division, or by procreation. (bring forth)

2. To increase in number or spread rapidly and often excessively.

Myelo

Bone Marrow

MPD

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Plasia:

formation or development:

Dysplasia:

a. refer to an abnormality of development:

b. generally consists of an expansion of immature cells, with a corresponding decrease in the number and location of mature cells:

c. Dysplasia is often indicative of an early neoplastic (new

growth) process.

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If you can raed this, you have a sgtrane mnid

Can you raed this? Olny 55 plepoe out of 100 can.

I cdnuolt blveiee that I cluod aulaclty uesdnatnrd what I was rdanieg. The phaonmneal pweor of the hmuan

mnid, aoccdrnig to a rscheearch at Cmabrigde Uinervtisy, it dseno't mtaetr in what oerdr the ltteres in a word are, the olny iproamtnt tihng is that the frsit and last ltteer be in the rghit pclae. The rset can be a taotl mses

and you can still raed it whotuit a pboerlm. This is bcuseae the huamn mnid deos not raed ervey lteter by istlef, but the word as a wlohe. Azanmig huh? Yaeh and

I awlyas tghuhot slpeling was ipmorantt!

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Normal blood cell development

Myeloproliferative disease can develop in any one of these cell types

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Enhanced proliferation/survival Normal Differentiation

Systemic mastocytosis

Polycythemia vera

Essential thrombocythemia

Hypereosinophilic syndrome

Myeloproliferative Diseases

Chronic myeloid leukemia

Chronic myelomonocytic leukemia

Myeloid metaplasia/myelofibrosis

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Myeloproliferative disorders are characterized by:

• Panhypercellularity of the bone marrow.

• Erythrocytosis, granulocytosis, and thrombocytosis in the peripheral blood.

• One cell line is usually more prominent than the others.

• Haematologic classification is based on the most prominent cell line

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Myeloproliferative Disorders

The myeloproliferative disorders include:

a. Chronic myelogenous leukaemia. (CML)

b. Polycythemia vera. + Secondary polycythemia

c. Myelofibrosis.

d. Essential thrombo-cythemia.

Because all of these entities might present with leukocytosis, differentiation can be difficult and usually requires special laboratory studies and bone marrow examinations.

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Prominent cell Disorder Myeloid series Chronic myelocytic leukemia. Erythroid (red cell) Polycythemia vera

Megakaryocytic Essential thrombocythemia.

Fibroblast Myelofibrosis with myeloid metaplasia.

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Features common to all myeloproliferative disorders are:

Occur gradually.

Occur in the middle aged or elderly.

Clinically the patients present with anaemia or polycythemia, leukocytosis and thrombocytosis with bizarre, abnormally functional platelets.

Hepatosplenomegaly.

Hypercellular bone marrow that might become fibrotic.

Might terminate in an acute leukaemia.

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General Definition:General Definition:

Clonal hematopoietic stem cell diseases that result in Clonal hematopoietic stem cell diseases that result in expansion and excessive production and over expansion and excessive production and over accumulation of accumulation of erythrocytes, granulocyteserythrocytes, granulocytes,, and and plateletsplatelets in some combination in the bone marrow, in some combination in the bone marrow, peripheral blood, and body tissues.peripheral blood, and body tissues.

They are grouped as myeloproliferative diseases because They are grouped as myeloproliferative diseases because they may express common clinical features, laboratory they may express common clinical features, laboratory changes, and pathogenetic similarities.changes, and pathogenetic similarities.

Clinically, patients with MPD present in a clinically stable Clinically, patients with MPD present in a clinically stable phase that might transform to an aggressive cellular phase that might transform to an aggressive cellular growth phase such as acute leukaemia or just a more growth phase such as acute leukaemia or just a more aggressive form of MPD.aggressive form of MPD.

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DefinitionsChronic myelogenous (or myeloid) leukaemia (CML) is a form of leukaemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.

Primary polycythemia, often called polycythemia vera (PCV), polycythemia rubra vera (PRV), or erythremia, occurs when excess red blood cells are produced as a result of an abnormality of the bone marrow.

Often, excess non-lymphoid white blood cells and platelets are also produced. Polycythemia vera is classified as a myeloproliferative disease.

The PCV is increased and the blood becomes more viscous.

Not to be confused with secondary Polycythemia.Continued over

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Secondary Polycythemia (Brief)Causes and symptoms

Smoking, which impairs red blood cells' ability to deliver oxygen to body tissues.Carbon monoxide poisoning. Chronic heart or lung disease. Hormonal (endocrine) disorders. Exposure to high altitudes. Kidney cysts. Tumors of the brain, liver, or uterus.

Causes of spurious polycythemia include:Burns. Diarrhoea. Haemoconcentration (higher-than-normal concentration of cells and solids in the blood, usually due to becoming dehydrated or taking diuretics). Stress.

Confirm that the high haemoglobin is due to an increased red cell

mass, and not

Haemoconcentration.

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Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, and primary myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by fibrous (scar) tissue.

Essential thrombocytosis (ET, also known as essential thrombocythemia) is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause.

In some cases this disorder may be progressive, and rarely might evolve into acute myeloid leukaemia or myelofibrosis.

It is one of four myeloproliferative disorders.

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Polycythemia Rubra VeraIncidence: peaks at 60-80 y: slightly commoner in males. 2/100,000 per year.

A neoplastic, clonal overproduction of erythrocytes, granulocytes, and platelets to some degree (primary problem is too many RBCs)

The clonal neoplastic transformation arises in a pluripotential hematopoietic stem cell. RBCs are very sensitive to erythropoietin for cell growth.

Clinical diagnosis:

Increased red cell mass. Maybe have increased arterial O2 saturation.Splenomegaly. (75%)Increased platelet counts or WBC counts.Disease progresses to acute leukemia in 15% of cases.Primary treatment is therapeutic phlebotomy.

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Complications Accelerated atherosclerotic and thrombotic disease.

Cerebrovascular Accident. (CVA)

Myocardial Infarction. (MI)

Peripheral Vascular Disease. (PVD)

Mesenteric thrombosis.

Hepatic vein thrombosis or Portal Vein Thrombosis.

Haemorrhage.

Epistaxis. (Nosebleeds)

Acute Gastrointestinal Bleed.

Progression to other haematologic disorder.

Myelofibrosis (20% of patients).

Leukaemia (15% of patients)

Hyperviscosity symptoms:Hyperviscosity symptoms: headache, dizziness, visual headache, dizziness, visual alterations, tinnitus, vertigo and alterations, tinnitus, vertigo and syncope; all indicate cerebral nervous syncope; all indicate cerebral nervous system hypoperfusion.system hypoperfusion.

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20% of patients would have thrombotic events at the 20% of patients would have thrombotic events at the time of presentation.time of presentation.30% will develop thrombosis during the coarse of the 30% will develop thrombosis during the coarse of the disease.disease.Cerebrovascular accidents, myocardial infarction, Cerebrovascular accidents, myocardial infarction, peripheral vascular disease, DVT, pulmonary embolism, peripheral vascular disease, DVT, pulmonary embolism, mesenteric vessels occlusion and Budd-Chiari mesenteric vessels occlusion and Budd-Chiari syndrome are seen in uncontrolled polycythemia.syndrome are seen in uncontrolled polycythemia.

Plethora of the face (Red Face)Plethora of the face (Red Face)Pruritis: after hot bath; due to hyper histaminemia.Pruritis: after hot bath; due to hyper histaminemia.Erythromelalgia: Pain and redness in the distal portions of Erythromelalgia: Pain and redness in the distal portions of the extremities.the extremities.Splenomegaly: 70% of patients.Splenomegaly: 70% of patients.Hepatomegaly in 40 % of patientsHepatomegaly in 40 % of patientsHypertension: usually corrected after treatment.Hypertension: usually corrected after treatment.

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Polycythemia Vera Film

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Rouleaux - Increased Fibrinogen & Globulins

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Laboratory features:Laboratory features:RBC:RBC:

RBC life span and morphology are normal.RBC life span and morphology are normal.Erythrocytosis.Erythrocytosis.Depletion of iron stores leads to microcytosis and Depletion of iron stores leads to microcytosis and hypochromia.hypochromia.

Platelets:Platelets:ThrombocytosisThrombocytosisLarge platelets might be present.Large platelets might be present.Abnormal platelets function as seen with platelets Abnormal platelets function as seen with platelets aggregation studies. aggregation studies. (thrombasthenia) defective platelet (thrombasthenia) defective platelet aggregation.aggregation.

GranulocytesGranulocytes::Elevated neutrophils, esinophils and basophils count.Elevated neutrophils, esinophils and basophils count.Increased Neutrophil alkaline phosphatase (NAP) score.Increased Neutrophil alkaline phosphatase (NAP) score.

Normal or low serum Erythropoietin level.Normal or low serum Erythropoietin level.

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Extramedullary Haematopoiesis occurs in the

Liver & Spleen

Teardrop cells are seen on the blood smear

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World Health Organization (WHO) criteria for diagnosis of

Polycythemia Vera

A1. elevated RBC mass > 25% above mean normal predicted value,or Hb > 185g/L ( Male ) Hb > 165 g/L (female )

A2. No cause of secondary erythrocytosis, including: Absence of familial erythrocytosis No elevation of EPO from - hypoxia ( PaO2 92 % )

- high O2 affinity Hb. - truncated EPO receptor

- inappropriate EPO production by tumor A3. Splenomegaly

A4. Clonal genetic abnormality other than Ph chromosome or BCR/ABL fusion gene in marrow cells

A5. Endogenous erythroid colony formation in vitro

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B1. Thrombocytosis > 400,000

B2. WBC > 12 x 109/L

B3. BM Biopsy showing panmyelosis with prominent erythroid & megakaryocytic proliferation

B4. Low serum EPO levels

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EPO Production secondary to hypoxia

Lung disease

High altitude

Smoking

Cyanotic Heart disease

Methemoglobinemia

High O2 affinity haemoglobin

Cobalt

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EPO Overproduction

Tumors ; renal , brain , hepatoma , uterine fibroid ,

pheochromocytoma

Renal artery stenosis

inappropriate EPO secretion

Bartter’s syndrome

Renal cyst , hydronephrosis

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Bartter syndrome is a rare inherited defect in the thick ascending limb of the loop of Henle.

It is characterized by low potassium levels (hypokalemia),

decreased acidity of blood (alkalosis),

normal to low blood pressure.

There are two types of Bartter syndrome: neonatal and classic.

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Polycythemia Vera (PV) Polycythemia Vera (PV) & Secondary polycythaemia& Secondary polycythaemia

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Typical Blood Count: (Polycythemia)

WBC 18.0 [4 - 11] Leukocytosis

Hb g/L 200 [140 - 180]

Hct (PCV) 0.62 [.42 - .51]

MCV fl 75 [80 - 100]

Platelets 850 [150 - 450] Thrombocytosis

Neuts x 109/L 14.6 [2 - 7.5] Neutrophilia

Lymphs x 109/L 2.0 [1.5 - 4]

Monos x 109/L 0.8 [0.2 - 0.8]

Eos x 109/L 0.1 [0 - 0.7

Basos x 109/L 0.5 [0 - 0.1]

Film Comment: microcytosis: large and abnormal platelets present

45%

62%

Normal

PCV

Poly

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Polycythaemia is a general term used to describe an erythrocytosis with increased RBCs and haemoglobin.

Need to distinguish between relative (due to decreased plasma volume) and absolute.

Is classified into 3 groups.

Relative – caused by dehydration, haemoconcentration.

Primary polycythemia (polycythaemia vera).

Secondary polycythaemia.

Both the primary and secondary forms result in an absolute increase in the number of RBCs.

The increase in RBCs is independent of erythropoietin stimulation

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Haemacrit (PCV) in polycythaemia

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Essential ThrombocythemiaEssential ThrombocythemiaAlso called essential thrombocytosis or primary Also called essential thrombocytosis or primary

thrombocytosis.thrombocytosis.

First described over 70 years ago.First described over 70 years ago.

A subgroup of the chronic myeloproliferative A subgroup of the chronic myeloproliferative disorders (CMPDs).disorders (CMPDs).

The most common myeloproliferative disorder.The most common myeloproliferative disorder.

The only CMPD that is a diagnosis of exclusion.The only CMPD that is a diagnosis of exclusion.

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Essential thrombocythemia is a clonal myeloproliferative disorder characterized by:

Bone marrow hyperplasia.

Excessive proliferation of megakaryocytes.

Sustained elevation of the platelet count.

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PathogenesisPathogenesis

Neither thrombopoietin (TPO), the key hormone in the regulation Neither thrombopoietin (TPO), the key hormone in the regulation of megakaryocyte differentiation and proliferation, nor its of megakaryocyte differentiation and proliferation, nor its

receptor, c-Mpl,receptor, c-Mpl,** has been implicated in the pathogenesis of ET. has been implicated in the pathogenesis of ET.

** The thrombopoietin receptor, c-Mpl, is a selective surface The thrombopoietin receptor, c-Mpl, is a selective surface marker for human haematopoietic stem cells.marker for human haematopoietic stem cells.

Mutations involving the c-Mpl gene have not been identified in Mutations involving the c-Mpl gene have not been identified in Essential ThrombocythemiaEssential Thrombocythemia

Serum TPO levels are inappropriately normal or elevated.Serum TPO levels are inappropriately normal or elevated.

Thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and Thrombopoietin (leukemia virus oncogene ligand, megakaryocyte growth and development factor), also known as THPO, is a glycoprotein hormone development factor), also known as THPO, is a glycoprotein hormone produced produced mainly by the liver and the kidney that regulates the production of platelets by mainly by the liver and the kidney that regulates the production of platelets by the bone marrow.the bone marrow. It stimulates the production and differentiation of megakaryocytes, It stimulates the production and differentiation of megakaryocytes, the bone marrow cells that fragment into large numbers of platelets.[the bone marrow cells that fragment into large numbers of platelets.[

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Epidemiology of Essential ThrombocythemiaEpidemiology of Essential Thrombocythemia

Incidence rate of 2.5 new cases/100,000 people per year.Incidence rate of 2.5 new cases/100,000 people per year.

In the US, approximately 6,000 people are diagnosed with In the US, approximately 6,000 people are diagnosed with Essential Thrombocythemia each year.Essential Thrombocythemia each year.

A female preponderance exists with a A female preponderance exists with a female to male ratiofemale to male ratio of approximately of approximately 2:1.2:1.

The median age at diagnosis is 60 years.The median age at diagnosis is 60 years.

Up to 20% of patients are younger than 40 years old.Up to 20% of patients are younger than 40 years old.

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Clinical PresentationClinical Presentation

Up to 50% of patients may be totally asymptomatic at Up to 50% of patients may be totally asymptomatic at presentation.presentation.

The remaining 50% of patients may have “vasomotor” The remaining 50% of patients may have “vasomotor” symptoms, thrombotic events, or hemorrhagic symptoms, thrombotic events, or hemorrhagic complications.complications.

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ESSENTIAL THROMBOCYTHEMIA

Laboratory findings

Thrombocytosis (in most patients patients >1000 x 10G/L).

Numerous thrombocyte aggregates in peripheral blood smear.

Leukocytosis, usually less than 20 x 10G/L.

Neutrophilia and a mild shift to the left (usually due to metamyelocyte).

Slight eosinophilia and basophilia.

Marked hyperplasia of the megakaryocytes in the bone marrow.

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Essential thrombocythemia blood film

Increased platelet number and clumps of large abnormal platelets.

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DiagnosisDiagnosis of essential thrombocythemia (ET) is made in the presence of nonreactive thrombocytosis and after the exclusion of another chronic myeloid disorder that might mimic ET in its presentation.

Reactive thrombocytosis is an increase in the circulating thrombocyte count secondary to a physiologic process within the body, often an infection. Reactive thrombocytosis is different than primary or essential thrombocytosis which is usually related to myeloproliferative neoplasia.

Clinically, ET is characterized by vasomotor symptoms, thrombohemorrhagic complications, recurrent foetal loss, and transformation of the disease into either myelofibrosis with myeloid metaplasia or acute myeloid leukaemia.

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Therapy

1. No treatment - asymptomatic( without thrombotic and bleeding complications), young (< 60 r.z.) 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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Chronic myelogenous leukaemia. (CML)(Chronic myeloid leukaemia)

CML is a clonal myeloproliferative disorder.

Characterised by an increase in the white cell count.

(increase in neutrophils and their precursors in the peripheral blood).

Occurs at all ages.

Presenting symptoms include weight loss, night sweats, gout, left hypochondrial pain.

Splenomegaly, often massive, present in >90% of cases.

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Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATIONMATURATION

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CML Blood film

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CML x 50

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CML – Laboratory findingsFull blood count:

Raised white cell count (often >50 x 109/L) – mainly neutrophils and myelocytes, usually prominent basophils.

Not to be confused with a Leukemoid Reaction

AnaemiaPlatelets – high, normal or low.

Low leucocyte alkaline phosphatase (LAP) / neutrophil alkaline phosphatase (NAP) score.

Hypercellular bone marrow with myeloid hyperplasia.

Cytogenetic analysis of bone marrow cells shows the Philadelphia chromosome in >95% of cells analysed.

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CML – Philadelphia Chromosome >95% of patients with CML would test positive for the Philadelphia chromosome (derived chromosome 22)

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CML – Course & PrognosisCourse of disease

Stable chronic phase

Blastic transformation

Accelerated phase

Acute leukaemia

Patients are typically well during the “chronic phase”

Main cause of death is transformation to acute leukaemia (80%AML, 20% ALL)

Median survival is currently about 4 years

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CML – Principles of treatmentControl and prolong chronic stable phase (non-curative)

Imatinib mesylate - (Gleevec) - Alpha interferon – Hydroxyurea

Eradicate malignant clone (curative)

Allogeneic stem cell transplantation

Imatinib mesylate (Gleevec)?

Alpha interferon?

In acute phase i.e. acute leukaemia

Treat as for acute leukaemia

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Myelofibrosis

Myeloproliferative disorder (monoclonal stem cell disorder) in which increased marrow fibrosis is dominant feature.

Rare

50-70 yrs

Clinical: fatigue, weakness, malaise, fever/night sweats, abdominal pain, anorexia/wt loss, nausea/vomiting.

Might be primary or secondary (breast cancer, prostate cancer, Hodgkin's disease, non-Hodgkin's lymphoma, autoimmune diseases).

Haematopoietic stem cells grow out of control, producing both immature blood cells and excess fibrous tissue—replacing normal marrow.

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MyelofibrosisExtramedullary haematopoeisis: hepatic and splenic enlargement, thoracic

paravertebral masses

BonesUniform or heterogeneous increased density

Spine (“sandwich sign” or diffuse density), pelvis, skull, ribs, proximal femur/humerus

Cortical thickening in long bones

Decreased T1 and T2 marrow signal

Bone marrow: biopsy needed to confirm diagnosis

Progressive bone marrow failure

severe anaemia / thrombocytopenia/leukopenia

risk of bleeding/infection

Slowly progressive diagnosis leading to death

No available treatment to effectively reverse progression; possible cure with bone marrow or stem cell transplantation (significant risks)

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MyelofibrosisErythrokinetic Classification of Myelofibrosis

Class I (42%)Highly expanded erythropoiesisCentrifugal active marrow displacementRed cell mass normal or increasedIneffective erythropoiesis

Class II (46%)Slightly increased erythropoiesisAxial erythropoiesisRed cell mass normal or decreasedPeripheral haemolysis

Class III (12%)Erythroid failureDecreased red cell volume

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Anatomo-clinical Classification of Myelofibrosis

Hyperplastic type (20%)Young age (<50)High expansion of erythropoiesisMild or no anemiaPossibly post-polycythemiaGood prognosis

Dysplastic type (50%)Megacaryocytic dysplasiaMild anemiaIntermediate prognosis

Aplastic type (30%)Erythroid failureSevere anemiaBad prognosis

Myeloid metaplasia (AMM), first described by Heuck in 1879, is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells.

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Clinical Features

30% asymptomatic, most with fever & night sweats.

Marked splenomegaly is common > 2nd splenic infarction.

other symptoms;

fatigue, anaemia, abdominal pain, wt. loss

bleeding, peripheral oedema, bone pain (osteosclerosis)

Classic blood smear: Leukoerythroblastic

Bone marrow: mild to marked fibrosis

Elevation of LDH, serum B12, alkaline phosphatase

20% Transformation to acute leukaemia

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TestsBone marrow > “ Dry tap “

Classic blood smear:

Tear drop

Nucleated Red Blood Cells (NRC)

leukoerythroblastic

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Normal Bone Marrow Fibrosis

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Myelofibrosis with myeloid metaplasia

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Myeloid Disorders Usual Features at Diagnosis

Disease BM cellularit

y

% Marrow Blasts

Maturation Morphology

Haemato-poiesis

Blood count (s)

Organo-megaly

Myeloproliferatie disorder

Usually increased

Normal or slightly increased (<10%)

Present Relatively normal

Effective One or more myeloid cell lines increased

Common

Myelodysplastic syndromes

Usually increased, occasionally decreased

Normal or increased (<20%)

Present Dysplasia of one or more myeloid lineage

Ineffective Cytopenia (S)

Uncommon

Myelodysplastic/ myeloproliferative disease

Usually increased

Normal or increased (<20%)

Present Dysplasia of one or more myeloid lineages frequent

Effective or ineffective; may vary among involved lineages

Variable Common

Acute myeloid leukaemia

Usually increased, occasionally decreased

Increased (≥ 20%)

Varies, frequently minimal

May or may not be associated with dysplasia in one or more myeloid lines

Ineffective or effective

Variable uncommon

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Chronic Idiopathic Myelofibrosis Prefibrotic Stage

Clinical findings Morphological findingsSpleen and liver:No or mild splenomegaly or hepatomegaly

Blood:• No or mild leukoerythroblastosis• No or minimal red blood cell poikilocytosis; few if any dacrocytes

Splenomegaly:Haematologic parameters variable, but often:• Mild anaemia• Mild to moderate leukocytosis• Mild to marked thrombocytosis

Bone marrow: Hypercellularity Neutrophilic proliferation Megakaryocytic proliferation and atypia (Clustering of megakaryocytes, abnormally lobulated megakaryocytic nuclei, naked megakaryocytic nuclei) Minimal or absent reticulum fibrosis

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Chronic Idiopathic Myelofibrosis Fibrotic Stage

Clinical findings Morphological findings

Spleen and liver:Moderate to marked splenomegaly and hepatomegaly

Blood: Leukoerythroblastosis Prominent red blood cell poikilocytosis with dacrocytes

Haematology:• Moderate to marked anaemia• Low, normal or elevated WBC• Platelet count decreased, normal or elevated

Bone Marrow: Reticulin and/or collagen fibrosis Decreased cellularity Dilated marrow sinuses with intraluminal haematopoiesis Prominent megakaryocytic proliferation and atypia (clustering of megakaryocytes, abnormally lobulated megakaryocytic nuclei, naked nuclei) New bone formation (osteosclerosis)

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When Extramedullary haematopoeisis occurs, teardrop cells appear in the peripheral blood.

Extramedullary haematopoeisis is red cells being made outside the Bone Marrow.

(Reticuloendothelial system) Liver, Spleen

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That’s it