Myeloproliferative diseases

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Myeloproliferative diseases
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Myeloproliferative disease
Clonal hematolopoietic stem cell diseases
Characterized by overproduction of one/more blood
cell lines
1st proposed in 1951 by William Dameshek
not a malignant neoplasm, MPDs are
classified within the Hematological
neoplasms
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Myeloproliferative disease
arise from precursors of the "myeloid" lineage
in the bone marrow

• Polycythemia vera (PV)
• 2. Essential thombocytosis (ET)
• 3. Myelofibrosis with myeloid
  metaplasia (MMM)
• 4. Chronic Myelomonocytic leukemia
  (CMML)

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BONE MARROW Hematopoiesis
Pluripotent Stem Cell
Baso.
CBL?
Myeloid Stem Cell
Myeloblast
Eos.
CEL
PMN
CNL
Erythro blast
Megalo blast
Mono.
RBC
Platelet
CML
CMML
PV
ET
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Polycythemia vera

• 1892 1st described by Vaquez
• 1900 Phlebotomy as treatment by Osler
• Dameshek classified PV as a MPD
• 1967 Wesserman defined of PV
  and treatment

incidence 2
per 100,000 etiology
unknown median age 60
yrs. ( male )
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Polycythemia vera
Survival time
1.5 yrs
untreated PV 3.5 yrs PV
with phlebotomy 7-12 yrs PV
with myelosuppression
10 20 ? abnormal
cytogenetics
Trisomy 8 , Trisomy 9 and deletion 20q
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Pathophysiology
Clonal stem cell disorder with trilineage
myeloid involvement
Characterized by GF-independent erythroid
proliferation producing an elevated red cell mass
Extramedullary hematopoiesis Liver ,
Spleen
Congenital PV abnormal of truncated form of
EPO receptor
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Clinical Features

• HT
• Thrombosis ? common cause of death
• Pruritis ( aggravated by bathing ) 50
  
• Erythromelagia
• Digital ischemia ( palpable pulse )
• Joint pain
• Weight loss
• Headache , vertigo
• Visual disturbance
• Conjunctival plethora
• Palpable splenomegaly 70

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Clinical Features

• 10 Budd-Chiari Synd. pts. have
  coexistent PV
• 33 PV pts. have Acquired VWD
• 20 Erythrocytosis alone
• 40 Trilineage hyperplasia
• BMA Hypercellularity
• atypical megakaryocyte clustering
• decrease stainable iron

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Clinical Features

• Lab elevated leukocyte alkaline phosphatase
  ( LAP ) 70
• elevated serum B12
  40
• Risk to transform to acute leukemia 1.5
• spent phase 10-25
• ( Spent phase normalization of red cell mass
  asso. with
• cytopenia , increasing splenomegaly
  (extramed.hemat.)
• collagen fibrosis of BM )

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WHO criteria for diagnosis of Polycythemia
Vera

• A1. elevated RBC mass gt 25 above mean normal
  predicted value,or Hb gt 18.5g/dL ( Male ) Hb
  gt 16.5 g/dL (female )
• A2. No cause of 2nd erythrocytosis,including
• Absence of familial erythrocytosis
• No elevation of EPO from - hypoxia ( PaO2 92
  )
• - high O2 affinity Hb.
• - truncated EPO receptor
• - inappropiated 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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WHO criteria for diagnosis of Polycythemia
Vera

• B1. Thrombocytosis gt 400,000
• B2. WBC gt 12,000
• B3. BM Biopsy showing panmyelosis with prominent
  erythroid megakaryocytic proliferation
• B4. Low serum EPO levels

Diagnosis A1A2 and any other of CAT. A
or A1A2 and any 2 of CAT. B
or gt 99th percentile of method specific
reference range of age ,gender,altitude of
residence
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EPO Production secondary to hypoxia

• Lung disease
• High altitude
• Smoking
• Cyanotic Heart disease
• Methemoglobinemia
• High O2 affinity hemoglobin
• Cobalt

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EPO Overproduction

• Tumors renal , brain , hepatoma , uterine
  fibroid ,
• pheochromocytoma
• Renal artery stenosis
• inappropriate EPO secretion
• Bartters syndrome
• Renal cyst , hydronephrosis

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EPO levels in PV LOW or NORMAL
EPO Overproduction

• Tumors renal , brain , hepatoma , uterine
  fibroid ,
• pheochromocytoma
• Renal artery stenosis
• inappropriate EPO secretion
• Bartters syndrome
• Renal cyst , hydronephrosis

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PV Secondary polycythemia
Finding PV 2nd Polycythemia
Splenomegaly Leukocytosis Thrombocytosis RBC volume arterial O2 sat B12 level LAP Bone Marrow EPO level Endogenous CFU-E growth increased normal increased increased Panhyperplasia decreased - - - normal normal normal normal normal normal -
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Lab evaluation of erythrocytosis

• - ABG
• Iron study
• serum EPO level
• Liver Kidney function
• Abdominal Ultrasound / CT
• BMA / BM biopsy
• Red cell mass

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Lab evaluation of Erythrocytosis
PCR for overexpression of PRV-1 (
CD 177 )
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Staging Prognosis
Hct. gt 45 risk to thrombosis ? Death
age gt 70 yrs. previous Hx. of
thrombosis important predictor of recurrent
thrombotic events
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Treatment
aim - reduce thrombotic risk slow leukemic
transformation - based on risk of
thrombosis
High risk -age gt 60yr. -Previous
Hx. thrombosis -CVD risk(smoking,DLD )

• Low risk
• age lt 60yr.
• no Hx thrombosis
• Plt. lt 1,500,000
• no CVD risk

Intermediate risk
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Treatment
Treatment of choice is Phlebotomy

Hct. lt 45 in men , lt 42 in women
Hydroxyurea is supplemented to
decreased Hct.
IFN alfa use for cytoreduction in younger
( decreased risk to leukemic transformation of
hydroxyurea )
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Treatment
Busulfan or P-32 in elderly pt. with
hydroxyurea intolerated
Low dose ASA ( 40 mg ) alleviate of
microvascular sequelae ( headache,
vertigo,visual disturbance , erythromelalgia )
Anagrelide used in all MPD to lowering
platelet count
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Treatment
Pruritis ( 50 of cases ) Cold water ,
antihistamine
Cholestyramine , PUVA , IFN-alfa
Recently........SSRI ( Fluoxetine 20 mg OD)
Elective Surgery keep
Hct. lt 45

( more than 2 mo. )
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Transformation to spent phase occur
10 yrs. after 1st Dx.
develop Cytopenia Splenomegaly
Hydroxyurea and Interferon
Splenectomy Low dose splenic
irradiation ? short term relief Stem
Cell Transplantation for advanced PV ( Curative
!! )
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Essential Thrombocytosis
In 1934 1st described by Epstein
Goedel
Hemorrhagic thrombocytopenia 1951
classified to MPD by Dameshek
incidence 1- 2.5
per 100,000 etiology
unknown median age
50- 60 yrs. ( no gender )
survival time gt 10
yrs. ...... 5 of clonal cytogenetic
abnormality ....
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Essential Thrombocytosis
Pathophysiology

• -
• clonal disorder
• polyclonal hematopoiesis in some pts.
• Dx. by exclusion
• No defining cytogenetic or morphologic
  feature

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Clinical Features

• 50 asymptomatic
• 40 vasomotor symptoms
• visual disturbance , headache ,
  palpitation ,
• erythromelalgia , livedo
  reticularis, acral paresthesia
• 15 thrombosis DVT , PE ,digital
  ischemia,
• portal vein
  thrombosis, stroke, MI
• - 5-10 major hemorrhage

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Clinical Features

• others recurrent 1st trimester abortion ,
• palpable splenomegaly
• risk of leukemia transformation is less than
  other MPD
• lt 5 transformation to spent phasee

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Diagnostic Testing
- Characterized by persistent nonreactive
thrombocytosis

• DDx. of thrombocytosis
• 1. asplenia
  2. acute hemorrhage
• 3. Hemolysis
  4. Infection
• 5. Post thrombocytopenic rebound 6. CA
• 7. Inflam. state ( infection,collagenvascu
  lar dz. )
• 8. Iron def. 9. Pregnancy 10.
  MPD

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Diagnostic Testing

• Lab assist in Dx.
• 1. Iron study
  2. CRP , ESR
• 3. PBS HJ bodies 4.
  Bone marrow
• 5. Cytogenetic FISH or PCR for
  BCR/ABL ( exclude CML )
• 6. decreased megakaryocyte c-mpl
  expression
• 7. increased granulocyte PRV-1
  endogenous erythroid colony
• formation

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WHO diagnostic criteria of Essential
Thrombocytopenia
Positive Criteria - Sustained platelet count
gt or 600,000 - BM biopsy specimen showing
proliferation mainly of the megakaryocytic
lineage with increased numbers of
enlarged,mature megakaryocytes
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WHO diagnostic criteria of Essential
Thrombocytopenia

• Exclusion criteria
• - No evidence of PV
• Normal red cell mass or Hb. lt 18.5 g/dL men
  , Hb. lt 16.5 g/dL women
• Stainable iron in marrow, normal serum
  ferritin or normal MCV
• If the former condition is not met, failure
  of iron trial to increase red cell mass or Hb
  level to the PV range
• - No evidence of CML
• No Philadelphia chromosome and no BCR/ABL
  fusion gene
• - No evidence of chronic idiopathic
  myelofibrosis
• Collagen fibrosis absence
• Reticulin fibrosis minimal or absence

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WHO diagnostic criteria of Essential
Thrombocytopenia

• - No evidence of MDS
• - No evidence that thrombocytosis is reactive
  because of,
• Underlying inflammation or infection
• Underlying neoplasm
• Prior spleenectomy

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Treatment

• - Based on risk-based management
• Life expectancy is nearly normal
  

• Low risk group
• age lt 40 yr.
• no Hx. of thrombosis
• no CVD risk
• plt. lt 1,500,000

• High risk group
• age gt 60 yr.
• Hx. of thrombosis

Intermediated risk
group
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Therapeutic options

• - Plateletepheresis ( in acute situation )
• Myelosuppressive agent
• ( alkylating agent, Hydroxyurea,
  radiophosphorus )
• - Maturation modulators ( IFN-alfa , Anagrelide
  )
• - Antiplatelet agents

Goal Platelet count lt 400,000
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Myelofibrosis with myeloid metaplasia
In 1879 1st described by G.
Hueck 1951 classified to MPD
incidence 0.5-
1.5 per 100,000 (higher
incidence ? exposed to radiation)
etiology unknown
median age 65 yrs. (
no gender ) survival time
3-5 yrs. .......develop
in late stage of PV or ET ......often referred
to Agnogenic myeloid metaplasia(AMM) or
Idiopathic myelofibrosis
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Myelofibrosis with myeloid metaplasia
Pathophysiology
- Marrow fibroblasts not derived from abnormal
clone
increased in PDGF,TGF-beta Cytokines
Marrow fibrosis
- 50 cytogenetic abnormality 13q-,20q-,trisomy
8 ,trisomy9
- high level of CD 34
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Clinical Features

• 30 asymptomatic , most with fever
  night sweats
• Marked splenomegaly is common ? 2nd splenic
  infarction

• other symptoms fatigue, anemia, abdominal
  pain, wt. loss
• bleeding , peripheral edema , bone pain
  (osteosclerosis)
• Classic blood smear Leukoerythroblastic
• Bone marrow mild to marked fibrosis
• Elevation of LDH , serum B12 , alkaline
  phosphatase
• 20 Transformation to acute leukemia

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Diagnostic Testing

• No standard for
  Diagnosis !
• Inaspirable marrow ? Dry tap
• Classic blood smear Tear drop , NRC ,
  leukoerythroblastic

• DDX. metastatic CA , Granulomatous dz. , CNT
  dz. , Lymphoma
• - PV ET can transform to MMM
• - Cytogenetics , FISH or PCR for BCR/ABL (
  exclude CML )

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Staging Prognostic factor

• often progress to marrow failure
• - Advanced age
• - Hypercatabolic symptoms
• - Anemia ( Hb. lt 10 )
• - Leukopenia ( WBC lt 4,000 )
  /Leukocytosis ( gt30,000)
• - Abnormal cytogenetic or presence of
  circulating blast
• Median survival in high risk lt 2 yr
• but in low risk gt
  10 yrs

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Treatment

• Palliation
• 30 anemia ? Combination of Androgen (
  Oxymethalone 50 mg qid )
• and Prednisolone ( 30
  mg/d )
• ( EPO is ineffective )

• Blood transfusion
• Hydroxyurea ,Busulfan , IFN or Melphalan
  Thrombocytosis
• 
  Leukocytosis
  Organomegaly
• - ongoing study Thalidomide

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Treatment

• Allogeneic stem cell transplantation for poor
  prog. patient
• ( Curative !! )
• Overall survival after transplant 60

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Chronic Myelomonocytic Leukemia
incidence 4 per
100,000 etiology
unknown median age
70 yrs. ( male 1-3 times )
survival time
12-18 mo.

• WHO classified in myelodysplastic/myelopr
  oliferative
• Most common extramedullary sites Spleen ,
  Liver L.N.
• 20-40 Clonal cytogenetic abnormality
  trisomy8,deletion 7q and
• translocations invol. 5q31-35 ( activate
  PDGFR-beta asso. eosinophilia )

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Clinical Features

• Fatigue , Fever , Wt. loss or night sweats
• Risk of infection from neutropenia
• Bleeding from thrombocytopenia
• 50 normal or decreased WBC
• PBS Monocytosis
• 15 30 progress to acute leukemia
  

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Diagnostic Testing
WHO diagnostic criteria

• - Persistent peripheral blood monocytosis ( gt
  1,000 ) for more
• than 3 mo.
• Absence of the Philadephia chromosome or BCR/ABL
  fusion gene
• Less than 20 blasts in blood or BM
• Dysplasia of one or more myeloid lineages
• Clonal cytogenetic abnormality
  

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Staging Prognostic factor
Factors that shorter survival
- Hb. lt 12 g/dL
- Lymphocyte count gt 2,500
- Medullary blast count 10
- Presence circulating immature myeloid
cells ....Median
survival time 12 mo.
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Treatment

• No effective treatment in modify natural course
  of disease

• Growth Factor used to treat cytopenia
  

• Low dose Chemotherapy used in preleukemic
  phase

• Hydroxyurea used in proliferative phase
  

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Treatment

• Low dose CMT cytarabine ,topotecan,fludarabine,i
  darubicin
• etoposide ? little
  success in long term
• ( rare to CR !! )

• Imatinib mesylate effective in rare CMML (
  PDGFR-B
• translocation)

• Stem Cell transplantation proved successful in
  some cases

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Thank You...