1. Myeloproliferative diseases
BY Dr.Omar Alshaer

2. 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 ”

3. Myeloproliferative disease
arise from precursors of the "myeloid" lineage in the bone marrow
Polycythemia vera (PV)
2. Essential thombocytosis (ET)
Myelofibrosis with myeloid metaplasia (MMM)
Chronic Myelomonocytic leukemia (CMML)

4. CML CMML PV ET 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

5. Polycythemia vera 1892 : 1st described by Vaquez
: Phlebotomy as treatment by Osler
: Dameshek classified PV as a MPD
1967 : Wesserman defined of PV and treatment
incidence : per 100,000
etiology : unknown
median age : yrs. ( male )

6. Polycythemia vera Survival time 1.5 yrs untreated PV
yrs PV with phlebotomy
yrs PV with myelosuppression
10 – 20 %  abnormal cytogenetics
; Trisomy 8 , Trisomy 9 and deletion 20q

7. Clonal stem cell disorder with trilineage myeloid involvement
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

8. Clinical Features Thrombosis  common cause of deathHT
Thrombosis  common cause of death
Pruritis ( aggravated by bathing ) %
Erythromelagia
Digital ischemia ( palpable pulse )
Joint pain
Weight loss
Headache , vertigo
Visual disturbance
Conjunctival plethora
Palpable splenomegaly %

9. 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

10. Clinical Features
Lab : elevated leukocyte alkaline phosphatase ( LAP ) 70%
elevated serum B %
Risk to transform to acute leukemia %
spent phase %
( Spent phase : normalization of red cell mass asso. with
cytopenia , increasing splenomegaly (extramed.hemat.) &
collagen fibrosis of BM )

11. WHO criteria for diagnosis of Polycythemia Vera
A1. elevated RBC mass > 25% above mean normal predicted value,or Hb > 18.5g/dL ( Male ) Hb > 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

12. WHO criteria for diagnosis of Polycythemia Vera
B1. Thrombocytosis > 400,000
B2. WBC > 12,000
B3. BM Biopsy showing panmyelosis with prominent erythroid & megakaryocytic proliferation
B4. Low serum EPO levels
Diagnosis : A1+A2 and any other of CAT. A
or A1+A2 and any 2 of CAT. B
or > 99th percentile of method specific reference range
of age ,gender,altitude of residence

13. EPO Production secondary to hypoxia
Lung disease
High altitude
Smoking
Cyanotic Heart disease
Methemoglobinemia
High O2 affinity hemoglobin
Cobalt

14. EPO Overproduction
Tumors ; renal , brain , hepatoma , uterine fibroid ,
pheochromocytoma
Renal artery stenosis
inappropriate EPO secretion
Bartter’s syndrome
Renal cyst , hydronephrosis

15. EPO levels in PV LOW or NORMAL
EPO Overproduction
Tumors ; renal , brain , hepatoma , uterine fibroid ,
pheochromocytoma
Renal artery stenosis
inappropriate EPO secretion
Bartter’s syndrome
Renal cyst , hydronephrosis

16. 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
Panhyperplasia
decreased -

17. Lab evaluation of erythrocytosis
- ABG
Iron study
serum EPO level
Liver & Kidney function
Abdominal Ultrasound / CT
BMA / BM biopsy
Red cell mass

18. PCR for overexpression of PRV-1 ( CD 177 )
Lab evaluation of Erythrocytosis
PCR for overexpression of
PRV-1 ( CD 177 )

19. Staging & Prognosis Hct. > 45% risk to thrombosis  Death
age > 70 yrs. & previous Hx. of thrombosis
; important predictor of recurrent thrombotic events

20. Treatment
aim ; - reduce thrombotic risk & slow leukemic transformation
- based on risk of thrombosis
Low risk
age < 60yr.
no Hx thrombosis
Plt. < 1,500,000
no CVD risk
High risk
-age > 60yr.
-Previous Hx. thrombosis
-CVD risk(smoking,DLD )
Intermediate risk

21. Treatment Treatment of choice is “ Phlebotomy “
Hct. < 45 % in men , < 42% in women
“ Hydroxyurea “ is supplemented to decreased Hct.
“ IFN –alfa “ use for cytoreduction in younger
( decreased risk to leukemic transformation of hydroxyurea )

22. 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

23. Treatment
Pruritis ( 50% of cases ) ; Cold water , antihistamine Cholestyramine , PUVA , IFN-alfa
Recently SSRI ( Fluoxetine 20 mg OD)
Elective Surgery : keep Hct. < 45 %
( more than 2 mo. )

24. ; occur ~ 10 yrs. after 1st Dx. Transformation to spent phase
; develop Cytopenia & Splenomegaly
; Hydroxyurea and Interferon
; Splenectomy
; Low dose splenic irradiation  short term relief
; “ Stem Cell Transplantation “ for advanced PV ( Curative !! )

25. Essential Thrombocytosis
In ; 1st described by Epstein & Goedel
“ Hemorrhagic thrombocytopenia “
; classified to MPD by Dameshek
incidence : per 100,000
etiology : unknown
median age : yrs. ( no gender )
survival time : > 10 yrs.
% of clonal cytogenetic abnormality ....

26. Essential Thrombocytosis
Pathophysiology -
clonal disorder
polyclonal hematopoiesis in some pts.
Dx. by exclusion
No defining cytogenetic or morphologic feature

27. 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
% major hemorrhage

28. Clinical Features others ; recurrent 1st trimester abortion ,
palpable splenomegaly
risk of leukemia transformation is less than other MPD
< 5 % transformation to spent phasee

29. Diagnostic Testing
- Characterized by persistent nonreactive thrombocytosis
DDx. of thrombocytosis
1. asplenia acute hemorrhage
3. Hemolysis Infection
5. Post thrombocytopenic rebound 6. CA
7. Inflam. state ( infection,collagenvascular dz. )
8. Iron def Pregnancy MPD

30. Diagnostic Testing Lab assist in Dx. 1. Iron study 2. CRP , ESR
3. PBS : HJ bodies 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

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

33. WHO diagnostic criteria of Essential Thrombocytopenia
Exclusion criteria
- No evidence of PV
Normal red cell mass or Hb. < 18.5 g/dL men , Hb. < 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

34. 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

35. Treatment - Based on risk-based management
Life expectancy is nearly normal
Low risk group
age < 40 yr.
no Hx. of thrombosis
no CVD risk
plt. < 1,500,000
High risk group
age > 60 yr.
Hx. of thrombosis
Intermediated
risk group

36. Therapeutic options - Plateletepheresis ( in acute situation )
Myelosuppressive agent
( alkylating agent, Hydroxyurea, radiophosphorus )
- Maturation modulators ( IFN-alfa , Anagrelide )
- Antiplatelet agents
Goal : Platelet count < 400,000

37. Myelofibrosis with myeloid metaplasia
In ; 1st described by G. Hueck
1951 ; classified to MPD
incidence : per 100,000
(higher incidence  exposed to radiation)
etiology : unknown
median age : yrs. ( no gender )
survival time : yrs.
develop in late stage of PV or ET
......often referred to Agnogenic myeloid metaplasia(AMM)
or Idiopathic myelofibrosis

38. 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+

39. 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

40. 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 )

41. Staging & Prognostic factor
often progress to marrow failure ;
- Advanced age
- Hypercatabolic symptoms
- Anemia ( Hb. < 10 )
- Leukopenia ( WBC < 4,000 ) /Leukocytosis ( >30,000)
- Abnormal cytogenetic or presence of circulating blast
Median survival in high risk < 2 yr
but in low risk > 10 yrs

42. 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

43. Treatment Allogeneic stem cell transplantation for poor prog. patient
( Curative !! )
Overall survival after transplant ~ 60%

44. Chronic Myelomonocytic Leukemia
incidence : per 100,000
etiology : unknown
median age : yrs. ( male 1-3 times )
survival time : mo.
WHO classified in myelodysplastic/myeloproliferative
Most common extramedullary sites : Spleen , Liver & L.N.
20-40% Clonal cytogenetic abnormality ; trisomy8,deletion 7q and
translocations invol. 5q ( activate PDGFR-beta :asso. eosinophilia )

45. 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

46. Diagnostic Testing WHO diagnostic criteria :
- Persistent peripheral blood monocytosis ( > 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

47. Staging & Prognostic factor
Factors that shorter survival :
- Hb. < 12 g/dL
- Lymphocyte count > 2,500
- Medullary blast count 10 %
- Presence circulating immature myeloid cells
....Median survival time mo.

48. 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

49. Treatment Low dose CMT ; cytarabine ,topotecan,fludarabine,idarubicin
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

50. MCQS
1- An increase in the number of circulating RBCs above established normal limits?
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

51. MCQS
1- An increase in the number of circulating RBCs above established normal limits?
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

52. MCQS
2_ Which condition is the most likely treatment regiemefor?- hydroxyurea,alpha interferon,anagelide:
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

53. MCQS
2_ Which condition is the most likely treatment regiemefor?- hydroxyurea,alpha interferon,anagelide:
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

54. MCQS
2_ Which condition is the most likely treatment regiemefor?- venesection, hydroxyurea,p32(radioactivephosphorus):
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

55. MCQS
2_ Which condition is the most likely treatment regiemefor?- venesection, hydroxyurea,p32(radioactivephosphorus):
Thrombocythemia
Reactive thrombocytosis
Acute leukemia
Polycythaemia

56. Thank You...