Myeloproliferative Myeloproliferative DisordersDisorders

OverviewOverview

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

PolycythemiaPolycythemia

An elevation in packed cell volume (PCV), rather than a raised

haemoglobin concentration, defines polycythaemia. A raised PCV ›0.52 in M, ›0.48 in F) should be referred to a haematologist for measurement of red cell mass by

radionuclide labelling of the red cells.

Red cell mass measurements more than 25% above the predicted value constitute true or absolute polycythaemia. When the PCV is raised but the red cell mass is not, the condition is known as apparent or relative polycythaemia and is secondary to a reduction in plasma volume.

Classification of true Classification of true polycythemiapolycythemia

• Familial/inherited • Mutant erythropoietin receptor • High oxygen affinity haemoglobin• Acquired Primary • Polycythaemia vera Secondary • Hypoxia cardiac pulmonary • Ectopic erythropoietin renal disease neoplasms

Polycythemia veraPolycythemia vera

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

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

• Highest incidence in ages 50-Highest incidence in ages 50-75, but 5% occur in pts < 40 yr75, but 5% occur in pts < 40 yr

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– GoutGout

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 ↑↑B12B12

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

or Hb >18.5 g/dL in M or >16.5 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

• Drawbacks:Drawbacks:– Increased risk of thrombosisIncreased risk of thrombosis– 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

• 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 & PCVPCV

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

• The main features are BM fibrosis, extramedullary haemopoiesis (production of blood cells within organs other than the BM), splenomegaly, and leucoerythroblastic blood picture (immature red and white cells in the peripheral blood)

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

Leucoerythroblastic blood film in a patient with idiopathic

myelofibrosis. Note the nucleated red blood cell and the

myelocyte

Causes of Causes of leukoerythroblastic blood leukoerythroblastic blood

picturepicture• Idiopathic myelofibrosis• • Bone marrow infiltration• • Severe sepsis• • Severe haemolysis• • Sick neonate

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.

Chronic myeloid Chronic myeloid leukemialeukemia

CML is a clonal malignant myeloproliferative disorder believed to originate in a single abnormal haemopoietic stem cell. The progeny of this abnormal stem cell proliferate over months or years such that, by the time the leukaemia is diagnosed, the BM is grossly hypercellular and the number of leucocytes is greatly increased in the peripheral blood. Normal blood cell

production is almost completely replaced by leukaemia cells, which, however, still function almost normally.

IncidenceIncidence

Presentation may be at any age, but the peak incidence is at age 50-70 years, with a slight male predominance. This leukaemia is very rare in children.

PresentationPresentation

• Common• • Fatigue• • Weight loss• • Sweating• • Anaemia• • Haemorrhage—eg easy bruising, discrete

ecchymoses• • Splenomegaly with or without hepatomegaly• Rare• • Splenic infarction• • Leucostasis• • Gout• • Retinal haemorrhages• • Priapism• • Fever

Clinical courseClinical course can be divided into a chronic or “stable”

phase and an advanced phase, the latter term covering both accelerated and blastic phases. Most patients present with chronic phase disease, which lasts on average 4-5 years. In about two-thirds of patients the chronic phase transforms gradually into an accelerated phase, characterised by a moderate increase in blast cells, increasing anaemia or thrombocytosis. After a variable number of months this accelerated phase progresses to frank acute blastic transformation. The remaining one-third of patients move abruptly from chronic phase to an acute blastic phase (or blastic crisis) without an intervening phase of acceleration

Massive splenomegalyMassive splenomegaly

PathogenesisPathogenesis

All leukaemia cells in patients with CMLcontain a specific cytogenetic marker, thePhiladelphia or Ph chromosome, which isderived from a normal 22 chromosome

that has lost part of its long arm as a result of a balanced reciprocal translocation of chromosomal material involving one of the 22 and one of the 9 chromosomes. The translocation is usually referred to as t(9;22)

LabLabUsual peripheral blood findings:• Raised WBC count (30000-400000).Differential shows:Granulocytes at all stages of developmentIncreased numbers of basophils and

eosinophilsBlast (primitive) cells (maximum 10%)—never

present in the blood of normal people• Haemoglobin concentration may be reduced;

red cell morphology is usually unremarkable; nucleated (immature) red cells may be present

• Platelet count may be raised (300000-600000)

InvestigationInvestigation to confirm suspected CMLRoutine• Full blood count including blood film• Neutrophil alkaline phosphatase• Urea, electrolytes• Serum lactate dehydrogenase• BM aspirate (degree of cellularity,

chromosomeanalysis)Optional• BM trephine biopsy (extent of fibrosis)• BCR-ABL chimeric gene by fluorescent in situHybridisation( FISH) or by PCR• Vitamin B12 and B12 binding capacity• HLA typing for patient and family members

TreatmentTreatment

Imatinib mesylate:Induces complete haematological

remission in 95% of previouslyuntreated patients and at least

50% of these will achieve a complete cytogenetic remission. Toxicity seems to be relatively mild.

TreatmentTreatment

Interferon-Interferon-аа restores spleen size and blood

counts to normal in 70-80% ofpatients. Some 10-20% of patients

achieve a major reduction orcomplete disappearance of cells

with the Ph chromosome from their BM

Currently interferon should be considered for chronic phase patients resistant to imatinib mesylate.

TreatmentTreatment

Allogeneic stem cell Allogeneic stem cell transplantationtransplantation

Patients under the age of 60 years who have siblings with identical HLA types may be offered treatment by high dose cytoreduction (chemotherapy

and radiotherapy) followed by transplantation of haemopoietic

stem cells collected from the donor’s BM or peripheral blood.

TreatmentTreatmentHydroxyureaHydroxyureaIt is useful for rapid reduction of the leucocyte count innewly diagnosed patients• start treatment with hydroxyurea then switch to

interferon once the patient’s symptoms are relieved and the leucocyte count is restored to normal

• Hydroxyurea is also valuable for controlling chronic phase

disease in patients who cannot tolerate interferon • started at 2.0 g daily by mouth; maintenance dose is

1.0-1.5 g daily.• Treatment with hydroxyurea does not eradicate cells

withthe Ph chromosome• Side effects are rare but include rashes, mouth

ulceration,and gastrointestinal symptoms.

Advanced diseaseAdvanced disease

Increasing splenomegaly despite full doses of cytotoxic drugs

• White blood cell count poorly responsive to full doses of cytotoxic drugs

• Anaemia or thrombocytopenia unresponsive to cytotoxic drugs

• Persistent thrombocytosis (1000000)• 10% blasts in peripheral blood or marrow• 20% blasts plus promyelocytes in blood

or marrow• Development of myelofibrosis