Myeloproliferative Myeloproliferative DisordersDisorders

OverviewOverview

• The Myeloproliferative The Myeloproliferative disorders:disorders:– Polycythemia veraPolycythemia vera– Essential ThrombocytosisEssential Thrombocytosis– MyelofibrosisMyelofibrosis– CMLCML

PolycythemiaPolycythemia

• Erythrocytosis is an increase in the concentration of erythrocytes, whether measured as number of cells, hemoglobin, or packed cell volume (hematocrit)

• Erythrocytosis may be the result of • an increase in the red cell volume or

mass (absolute erythrocytosis), or • may be the result of a reduced

plasma volume (called relative or spurious polycythemia or Geisböck's syndrome )

• Polycythemia accompanies increased total blood volume, whereas relative erythrocytosis does not

• Secondary polycythemias are caused by factors extrinsic to red cell precursors

• Physiologically-appropriate (in response to tissue hypoxia )

• Physiologically-inappropriate

PolycythemiaPolycythemia

• ERYTHROPOETIN (EPO)-mediated :• Hypoxia driven:• Central hypoxic process• Chronic lung disease• Rt-to-lt cardiopulmonary shunts• High-altitude habitat• Carbon monoxide poisoning• Smoker’s polycythemia (long-term CO

exposure) • Hypoventilation syn including sleep

apnea• Hemoglobinopathy(High–O² affinity

variety)

• Peripheral hypoxic process:• Localized:• Renal artery stenosis• Diffuse:• High oxygen-affinity

hemoglobinopathy

• Hypoxia independent (pathologic EPO production):

• Malignant tumors: • Hepatocellular carcinoma • Renal cell cancer • Cerebellar hemangioblastoma • Parathyroid carcinoma • Nonmalignant conditions :• Uterine leiomyomas • Renal cysts (polycystic kidney

disease) • hydronephrosis • Pheochromocytoma • Meningioma

Polycythemia veraPolycythemia vera

• Definition: A neoplastic disorder Definition: A neoplastic disorder arising from a pluripotent stem arising from a pluripotent stem cell, generally characterized by cell, generally characterized by erythrocytosis, with or without erythrocytosis, with or without thrombocytosis and leukocytosis.thrombocytosis and leukocytosis.

• Incidence 10 new cases per Incidence 10 new cases per millionmillion

• Highest incidence in ages 50-75, Highest incidence in ages 50-75, but 5% occur in pts < 40 y.o.but 5% occur in pts < 40 y.o.

P vera - natural historyP vera - natural history• Latent phase - asymptomaticLatent phase - asymptomatic• Proliferative phaseProliferative phase - pts may be - pts may be

hypermetabolic or have sx of hypermetabolic or have sx of hyperviscosity or thrombosishyperviscosity or thrombosis

• Spent phaseSpent phase - anemia, - anemia, leukopenia, secondary leukopenia, secondary myelofibrosis, increasing liver myelofibrosis, increasing liver and spleen sizeand spleen size

• Secondary AMLSecondary AML– 1-2% of pts treated with phlebotomy 1-2% of pts treated with phlebotomy

alonealone– Certain drug therapies increase riskCertain drug therapies increase risk

P vera - symptomsP vera - symptoms

• Sx common to all erythrocytosisSx common to all erythrocytosis– Headache, Headache, mental acuity, weaknessmental acuity, weakness

• Sx more specific to P vera:Sx more specific to P vera:– Pruritus Pruritus after bathingafter bathing– ErythromelalgiaErythromelalgia– Hypermetabolic symptomsHypermetabolic symptoms– ThrombosisThrombosis (arterial or venous) (arterial or venous)– HemorrhageHemorrhage

ErythromelalgiaErythromelalgia

P vera – signs:P vera – signs:

• Facial plethoraFacial plethora• Splenomegaly (70%)Splenomegaly (70%)• Hepatomegaly (40%)Hepatomegaly (40%)• Distension of retinal veinsDistension of retinal veins

P vera - Lab FindingsP vera - Lab Findings• CBCCBC

Hgb/HctHgb/Hct– î red cell massî red cell mass WBC in 45%WBC in 45% Plts in 65%Plts in 65%– BasophiliaBasophilia (seen in all MPDs) (seen in all MPDs)

Uric acid (can lead to gout) and Uric acid (can lead to gout) and îB12îB12

Leukocyte alkaline phosphatase Leukocyte alkaline phosphatase scorescore

• Low Epo levelsLow Epo levels• Positive JAK2 Positive JAK2

DiagnosisDiagnosis

– Major CriteriaMajor Criteria• Increased Red Cell Mass (>36ml/kg Increased Red Cell Mass (>36ml/kg

males, >32 ml/kg females)males, >32 ml/kg females)• Arterial oxygen saturation > 92%Arterial oxygen saturation > 92%• SplenomegalySplenomegaly

– Minor CriteriaMinor Criteria• Platelets > 400,000Platelets > 400,000• WBC > 12,000WBC > 12,000• LAP score > 100LAP score > 100• Serum B12 > 900 or serum unbound B12 Serum B12 > 900 or serum unbound B12

binding capacity >2200binding capacity >2200

WHO criteriaWHO criteria

• A criteria • A1 - Elevated red blood cell mass

(>25% more than the mean normal predicted value) or Hb >18.5 g/dL in M or >16.5 g/dL in F

• A2 – No cause of secondary erythrocytosis

• A3 - Splenomegaly • A4 - Clonal genetic abnormality

other than Ph-chromosome or BCR/ABL fusion gene in marrow cells

WHO criteriaWHO criteria

• B criteria • B1 - PLT > 400000 and WBC >12000 • B2 - BM biopsy showing

panmyelosis with prominent erythroid and megakaryocytic proliferation

• B3 - Low serum EPO levels • A diagnosis of PV is made when• A1 + A2 + any one A• A1 + A2 + any two B

P vera - TreatmentP vera - Treatment

• PhlebotomyPhlebotomy• Myelosuppressive agentsMyelosuppressive agents

– HydroxyureaHydroxyurea– Alkylating agents such as Alkylating agents such as

busulfanbusulfan– 3232PP

• Interferon alphaInterferon alpha

P vera - phlebotomyP vera - phlebotomy• Generally, the best initial Generally, the best initial

treatment:treatment:– No increase in progression to AMLNo increase in progression to AML– Rapid effectRapid effect– No BM suppressionNo BM suppression

• Remove 500 cc blood 1x/wk to Remove 500 cc blood 1x/wk to target Hct <45%, then maintaintarget Hct <45%, then maintain

• Downsides:Downsides:– Increased risk of thrombosisIncreased risk of thrombosis– No effect on progression to spent No effect on progression to spent

phasephase– May be insufficient to control diseaseMay be insufficient to control disease

P vera - P vera - MyelosuppressionMyelosuppression

• Hydroxyurea Hydroxyurea – can be used in conjunction with can be used in conjunction with

phlebotomyphlebotomy– May increase the risk of leukemic May increase the risk of leukemic

transformation from 1-2% to 4-5%transformation from 1-2% to 4-5%

• 3232PP– increase the risk of leukemic increase the risk of leukemic

transformation from 1-2% to 11%transformation from 1-2% to 11%– May be appropriate for pts intolerant May be appropriate for pts intolerant

of medications or for elderly patientsof medications or for elderly patients– Single injection may control Single injection may control

hemoglobin and platelet count for a hemoglobin and platelet count for a year or more.year or more.

P vera - interferon alphaP vera - interferon alpha• BenefitsBenefits

– No myelosuppressionNo myelosuppression– No increase in progression to No increase in progression to

AMLAML– No increase in thrombosis riskNo increase in thrombosis risk– OK in pregnancyOK in pregnancy

• DrawbacksDrawbacks– Must be given by injectionMust be given by injection– Side effects may be intolerable Side effects may be intolerable

in many pts, include flu-like in many pts, include flu-like symptoms, fatigue, fever, symptoms, fatigue, fever, myalgias, malaisemyalgias, malaise

Essential Essential ThrombocythemiaThrombocythemia

• Only 50% of these pts have a Only 50% of these pts have a clonal disorder--the rest have clonal disorder--the rest have polyclonal increase in polyclonal increase in megakaryocytesmegakaryocytes

• Incidence is similar to P veraIncidence is similar to P vera• 20% of pts are <40 y.o.20% of pts are <40 y.o.• Exact pathophysiology is Exact pathophysiology is

unclearunclear

ET - DiagnosisET - Diagnosis• First, rule out secondary causes First, rule out secondary causes

of thrombocytosisof thrombocytosis: cancer, : cancer, infection, inflammation, bleeding, infection, inflammation, bleeding, iron deficiencyiron deficiency

• Pts may have splenomegalyPts may have splenomegaly• Plts count should be >600000 on Plts count should be >600000 on

2 separate occasions, at least 1 2 separate occasions, at least 1 month apartmonth apart

• Exclude CML by absence of Exclude CML by absence of Philadelphia chromosomePhiladelphia chromosome

• Exclude P vera by normal Hb Exclude P vera by normal Hb without iron deficiency.without iron deficiency.

ET - natural historyET - natural history

• Rarely progresses to AML Rarely progresses to AML (<1% of pts)(<1% of pts)

• May progress to May progress to myelofibrosismyelofibrosis

• Major complication is Major complication is thrombosisthrombosis– in 20-30% of ptsin 20-30% of pts

- may be arterial or venous- may be arterial or venous

ET - SymptomsET - Symptoms

• Many patients are Many patients are asymptomaticasymptomatic

• Digital ischemia from Digital ischemia from microvascular thrombimicrovascular thrombi

• ErythromelalgiaErythromelalgia• PruritusPruritus• Hemorrhage - in 40% of ptsHemorrhage - in 40% of pts

ET - LabsET - Labs• Iron studies should be normal, as Iron studies should be normal, as

should the ESR, which is a measure of should the ESR, which is a measure of inflammation.inflammation.

• If the plt count is very high, there may If the plt count is very high, there may be be pseudohyperkalemia and pseudohyperkalemia and pseudohypoglycemiapseudohypoglycemia. This goes away . This goes away if the blood is drawn into a heparinized if the blood is drawn into a heparinized tube.tube.

• Plts can be very large and bizarrely Plts can be very large and bizarrely shapedshaped

• Marrow shows clusters of abnormal Marrow shows clusters of abnormal megakaryocytes.megakaryocytes.

• 50-75% may have JAK2 mutation50-75% may have JAK2 mutation

ET - Abnormal ET - Abnormal MegakaryocytesMegakaryocytes

Arrows Arrows indicate indicate some of some of the the abnormal abnormal mega-mega-karyocyteskaryocytes

ET - TreatmentET - Treatment• Treatment targeted at reducing Treatment targeted at reducing

the platelet count.the platelet count.• Treat those who Treat those who have had or are have had or are

at risk for thrombosisat risk for thrombosis, those , those >65 >65 y.oy.o., or pts with ., or pts with plts > 1-1.5 plts > 1-1.5 millionmillion

• Why treat?Why treat?– In pts at risk for thrombosis, Rx In pts at risk for thrombosis, Rx

reduces risk of thrombosis and may reduces risk of thrombosis and may reduce 2º myelofibrosis.reduce 2º myelofibrosis.

ET - therapeutic agentsET - therapeutic agents

•AnagrelideAnagrelide•HydroxyureaHydroxyurea• Interferon alphaInterferon alpha

ET - anagrelideET - anagrelide

• Interferes with megakaryocyte Interferes with megakaryocyte development without causing development without causing depression of other cell linesdepression of other cell lines

• Side effects include: hypotension, Side effects include: hypotension, severe headache, fluid retention, severe headache, fluid retention, palpitations/arrhythmias, severe palpitations/arrhythmias, severe headaches, CHF, headaches, CHF, bloating/diarrhea (in lactose bloating/diarrhea (in lactose intolerant patients)intolerant patients)

MyelofibrosisMyelofibrosis

• Clonal stem cell disorder affecting Clonal stem cell disorder affecting megakaryocytes predominantlymegakaryocytes predominantly

• All myeloproliferative disorders can All myeloproliferative disorders can result in a spent phase which can be result in a spent phase which can be difficult to distinguish from primary MFdifficult to distinguish from primary MF

• Myeloid metaplasia refers to earlier Myeloid metaplasia refers to earlier proliferative phase where proliferative phase where extramedullary hematopoiesis extramedullary hematopoiesis predominates.predominates.

MF - Natural Hx and SxMF - Natural Hx and Sx

– Median survival is 5 yrsMedian survival is 5 yrs– Transforms into AML in 5-20%Transforms into AML in 5-20%– >50% pts present with sx of >50% pts present with sx of

anemia and thrombocytopeniaanemia and thrombocytopenia– Pts may have fever, sweats, wt Pts may have fever, sweats, wt

lossloss– As spleen enlarges (from EMH), As spleen enlarges (from EMH),

pts may have abdominal pain, pts may have abdominal pain, early satiety.early satiety.

MF - Physical FindingsMF - Physical Findings

• Massive splenomegalyMassive splenomegaly• HepatomegalyHepatomegaly

MF - Lab findingsMF - Lab findings• Early on, pts may have Early on, pts may have Plts and Plts and

normal Hb and WBC.normal Hb and WBC.• Anemia, and Anemia, and Plts and Plts and WBC seen as WBC seen as

disease progressesdisease progresses• Peripheral smear shows Peripheral smear shows

leukoerythroblasticleukoerythroblastic picture, with picture, with teardrops, NRBC and early teardrops, NRBC and early granulocytesgranulocytes

• ““Dry tap” or inability to aspirate liquid Dry tap” or inability to aspirate liquid marrow frequently seenmarrow frequently seen

• Increased collagen and reticulin Increased collagen and reticulin fibrosis on BM biopsyfibrosis on BM biopsy

• 40-75% may have JAK2 mutation40-75% may have JAK2 mutation

Tefferi A. N Engl J Med 2000;342:1255-1265

Pathological Features of Peripheral Blood and Bone Marrow in Patients with Myelofibrosis with Myeloid Metaplasia

MF - TreatmentMF - Treatment

• There is no definitive therapyThere is no definitive therapy• If patient is young, BM transplant If patient is young, BM transplant

can be done, but older patients can be done, but older patients have too high mortalityhave too high mortality

• Rx is supportive, with Rx is supportive, with transfusionstransfusions

• Splenectomy can be done for sx Splenectomy can be done for sx of abdominal pain, but frequent of abdominal pain, but frequent complications of thrombosis, complications of thrombosis, hemorrhage, and infection.hemorrhage, and infection.