CHRONIC MYELOPROLIFERATIVE DISORDERS

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CHRONIC MYELOPROLIFERATIVE DISORDERS

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CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD)

• 1. Polycythemia vera
• 2. Chronic myeloid leukaemia
• 3. Essential thrombocythemia
• 4. Idiopathic myelofibrosis

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CHRONIC MYELOPROLIFERATIVE DISORDERS (MPD)

• MPD 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 smokers
  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 21. 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 poptic 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

• Splenomegaly is present in 75 of patients at
  the time of diagnosis.
• Hepatomegaly - is present in approximately 30 of
  patients at the time of diagnosis.
• Hypertension
• 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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DIAGNOSTIC CRITERIA FOR POLYCYTHEMIA
VERA(Polycythemia Vera Study Group 75)

• CATEGORY A
• 1. Total red cell mass
• male ? 36ml/kg
• female ? 32 ml/kg
• 2. Arterial oxygen saturation ? 92
• 3. Splenomegaly
• CATEGORY B
• 1. Thrombocytosis (platelet count gt 400 G/l)
• 2. Leukocytosis (white cell count gt 12 G/l, no
  fever or infection)
• 3. Increased leukocyte alkaline phosphatase
  (scoregt 100 )
• 4. Serum vitamin B12gt 900 pg/ml or vitamin B12
  binding capacity gt2200 pg/ml
• PV is diagnosed when A1A2A3 or A1A2 and any
  two from category B

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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 every
  other day until the
• hematocrit is less than 46
• - older patients or these with underlying
  cardiovascular disase should
• undergo smaller phlebotomies 200-300mL twice
  weekly or
• 100-150mLevery day until Htlt46
• - 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

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POLYCYTHEMIA VERA -therapy (2)

• IV. Antiplatelets agents
• Aspirin initially 150-300mg/d,
• maintence therapy 75-100 mg
• Tiklid 2x1
• Dipyridamol
• Anagrelide 2-2,5 mg/d
• V. Other modalities
• 1. Radioactive phosphorus (in older than 75
  years)
• 2. Interferon alpha 3 million units 3 times
  weekly
• VI. Special Topics
• 1. Pruritusantihistaminic agent,
  cyproheptadine-4mg three times per day
• 2. Hyperuricemia-allopurinol 300mg/day

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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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Myelofibrosisagnogenic myeloid metaplasia
(primary myelofibrosis, osteomyelofibrosis,
idiopathic myelofibrosis, myelofibrosis with
myeloid metaplasia )

• Myelofibrosis is a chronic myeloproliferative
  disease 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 giant),
  hepatomegaly(in about 50 of patients), symptoms
  of anaemia and thrombocytopenia

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MYELOFIBROSIS- laboratory findings (1)

• Anemia - Hblt10g/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 smearanisocytosis 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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MYELOFIBROSIS - diagnosis (Polycythemia Vera
Study Group criteria)

• Myelofibrosis involving more than one-third of
  the sectional area of a bone marrow biopsy
• a leukoerythroblaststic blood picture
• splenomegaly
• absence of the well-established diagnostic
  criteria for the MPD(i.e absence of increased red
  cell mass or the Ph chromosome),with systemic
  disorders excluded

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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. Hydroksyurea (15- 20mg/kg) for the control of
  leukocytosis, thrombocytosis, or organomegaly
• 4. Allopurinol-to prevent hyperuricaemia
• 5. Vit. D3-analogues(1,25-dihydroxycholecalciferol
  -1ug/d (?)
• 6. 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. Experimental therapies Interferon-?,
  antifibrotic and antiangiogenic drugs
  (anagrelide, suramin, pirfenidone, thalidomide,)

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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 disorder
  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 patientsgt1000
  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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ESSENTIAL THROMBOCYTHEMIA (UPDATED DIAGNOSTIC
CRITERIA)

• 1. Platelets countgt 600 G/l
• 2. Htlt40, or normal RBC mass(maleslt 36mL/kg,
  femaleslt32 mL/kg)
• 3. Stainable iron in marrow or normal serum
  ferritin or normal mean corpuscular
• volume (MCV)
• 4. No Philadelphia chromosome or bcrr/abl gene
  reagement
• 5. Collagen fibrosis of marrow
• A. Absent or
• B. lt 1/3 biopsy area without both marked
  splenomegaly and leukoerythroblastic
• reaction
• 6. No cytogenetic or morphologic evidence
  for myelodysplastic syndrome (5q-)
• 7. No cause for reactive thrombocytosis

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ESSENTIAL THROMBOCYTHEMIA -THERAPY

• 1. No treatment- asymptomatic( without thrombotic
  and bleeding
• complications), young (lt 60 r.z.) patients
  with platelet countlt1000G/L
• 2. Cytoreductive therapy patients with platelet
  countgt1000 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.