Myeloproliferative disordes explained well

1. Myeloproliferative disorders

2. Introduction
 Hemopoietic stem cell disorder
 Clonal
 Characterized by proliferation
 Granulocytic
 Erythroid
 Megakaryocytic
 Interrelationship between
 Polycythaemia
 Essential thrombocythaemia
 myelofibrosis

3. Introduction / haemopoiesis

4. Introduction
 Normal maturation (effective)
 Increased number of
 Red cells
 Granulocytes
 Platelets
(Note: myeloproliferation in myelodysplastic syndrome is ineffective)
 Frequent overlap of the clinical, laboratory &
morphologic findings
 Leucocytosis, thrombocytosis, increased
megakaeryocytes, fibrosis & organomegaly blurs
the boundaries
 Hepatosplenomegaly
 Sequestration of excess blood
 Extramedullary haematopoiesis
 Leukaemic infiltration

5. Rationale for classification
 Classification is based on the
lineage of the predominant
proliferation
 Level of marrow fibrosis
 Clinical and laboratory data (FBP,
BM, cytogenetic & molecular
genetic)

6. Differential diagnosis
Features distinguishing MPD from MDS, MDS/MPD & AML
Disease cellularity
BM
%
marrow
blasts
Maturation Morphology Haemato-
poiesis
Blood
counts
Large
organs
MPD Increase
d
Normal
or
< 10%
Present Normal Effectiv
e
One or
more
myeloid
increase
d
Common
MDS Usually
increased
Normal
or <
20%
Present Abnorma
l
In-
effective
Low one
or more
cytopeni
a
Un-
common
MDS/
MPD
Usually
increased
Normal
or <20%
Present Abnorma
l
Effective
or in-
effective
Variable Common
AML Usually
increased
Increase
d >20%
Minimal Dysplasia
can be
present
In-
effective
Variable Un-
common

7. Clonal evolution
Clonal evolution & stepwise progression to fibrosis, marrow failure or
acute blast phase

8. Incidence and epidemiology
 Disease of adult
 Peak incidence in 7th decade
 6-9/100,000

9. Pathogenesis
 Dysregulated proliferation
 No specific genetic abnormality
 CML (Ph chromosome t(9;22) BCR/ABL)
 Growth-factor independent proliferation
 PV, hypersensitiviy to IGF-1
 Bone marrow fibrosis in all MPD
 Fibrosis is secondary phenomena
 Fibroblasts are not from malignant clone
 TGF-β & Platelet like growth factor

10. Prognosis
 Depends on the proper diagnosis
and early treatment
 Role of
 IFN
 BMT
 Tyrosine kinase inhibitors

11. Myeloproliferative disorders
 Clonal haematopoeitic disorders
 Proliferation of one of myeloid lineages
 Granulocytic
 Erythroid
 Megakaryocytic
 Relatively normal maturation

12. Myeloproliferative disorders
WHO Classification of CMPD
 Ch Myeloid leukemia
 Ch Neutrophillic leukemia
 Ch Eosinophillic leukemia / Hyper Eo Synd
 Polycythemia Vera
 Essential Thrombocythemia
 Myelofibrosis
 CMPD unclassifiable

13. Myeloproliferative disorders
MPD
•PRV
•ET
•MF
AML
MDS
•RA
•RARS
•RAEB I
•RAEB II
CMML
CML

14. Myeloproliferative disorders
 Ch Myeloid leukemia (BCR-ABL positive)
 Polycythemia Vera
 Essential Thrombocythemia
 Myelofibrosis
 Specific clincopathologic criteria for diagnosis and distinct
diseases, have common features
 Increased number of one or more myeloid cells
 Hepatosplenomegaly
 Hypercatabolism
 Clonal marrow hyperplasia without dysplasia
 Predisposition to evolve

15. Bone marrow stem cell
Clonal abnormality
Granulocyte
precursors
Red cell
precursors
Megakaryocytes Reactive
fibrosis
Essential
thrombocytosis
(ET)
Polycythaemia
rubra vera
(PRV)
Myelofibrosis
AML
Chronic myeloid
leukemia
70%
10% 10%
30%

16. Epidemiology of CML
 Median age range at presentation: 45 to 55 years
 Incidence increases with age
 12% - 30% of patients are >60 years old
 At presentation
 50% diagnosed by routine laboratory tests
 85% diagnosed during chronic phase

17. Ionizing radiation Latent Period
Atomic bomb survivors 11 years ( 2-25)
Ankylosing spondylitis pts 3.6 years (1-6)
No evidence of other genetic factors
Chemical have not been associated with CML
Incidence 1-1.5/100,000 population
Male predominance
Epidemiology of CML

18. Presentation
Insidious onset
Anorexia and weight loss
Symptoms of anaemia
Splenomegaly –may be massive
Pt . maybe asymptomatic

20. The Philadelphia Chromosome
2 3 4 5
1
7 8 9 10 11 12
6
13 14 15 16 17 18
20 21 22 X Y
19

21. The Philadelphia Chromosome: t(9;22) Translocation
bcr-abl
Fusion protein
with tyrosine
kinase activity
22
bcr
abl
Ph
9 9+
Philadelphia
chromosome

22. Clinical Course: Phases of CML
Chronic phase
Median 4–6 years
stabilization
Accelerated phase
Median duration
up to 1 year
Blastic phase (blast crisis)
Median survival
3–6 months
Terminal phase
Advanced phases

23. Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865
Radiotherapy Pusey, 1902
Busulfan Galton, 1953
Hydroxyurea Fishbein et al, 1964
Autografting Buckner et al, 1974
Allogeneic BMT (SD) Doney et al, 1978
Interferon Talpaz et al, 1983
Allogeneic BMT (UD) Beatty et al, 1989
Donor Leukocytes Kolb et al, 1990
Imatinib Druker et al, 1998
Imatinib/Combination therapy O’Brien et al, 200……

24. CML Treatment
•Chemotherapy to reduce WCC - Hydroxyurea
•Interferon based treatment
•Allogeneic bone marrow transplant
•Molecular therapy - Imatinib

25. CML- CP survival post BMT
(IBMTR 1994-1999)
Years
Probability
%

26. Issues related to BMT
• 70% long term cure rate
• Donor Availability
• Age of patient
• Length/stage of disease
• Treatment related mortality
• Long term sequalae – infertility, cGVHD

27. The Ideal Target for Molecular Therapy
 Present in the majority of patients with a
specific disease
 Determined to be the causative abnormality
 Has unique activity that is
- Required for disease induction
- Dispensable for normal cellular function

28. Mechanism of Action of Imatinib
Goldman JM. Lancet. 2000;355:1031-1032.
Bcr-Abl
ATP
Substrate
Imatinib
Y = Tyrosine
P = Phosphate
Bcr-Abl
Substrate
P
P
P
P

29. Imatinib compared with interferon and low dose
Cytarabine for newly diagnosed chronic-phase
Chronic Myeloid leukemia
S.G. O’Brien et al
New England Journal of Medicine
Vol. 348 March 2003

30. Imatinib vs Interferon in newly diagnosed CP
Chronic Myeloid leukemia (18 months)
CHR 96% 67%
MCR 83% 20%
CCR 68% 7%
Intolerance 0.7% 23%
Progressive 1.5% 7%
disease
Imatinib 400mg Interferon and Ara-C

31. Evolution of treatment goals
HR MCR CCR PCR -
HU
IFN
Imatinib
BMT

32. Issues related to Imatinib
• Very few molecular responses (5-10%)
• Resistance in some patients
• Lack of response in some patients
• Expensive
• Long term toxicity/side effects unknown

33. CML
Diagnosis
Young with a
well-matched donor
Start Imatinib at
400mg/day
Cosider for Allograft
Allo SCT
Poor response or
Initial response
Followed by
Loss of response
Add or substitute
Other agents
Allo-SCT
Auto
Good response
maintained
Continue Imatinib
indefinitely

34. Polycythemia
 True / Absolute
 Primary Polycythemia
 Secondary Polycythemia
 Epo dependent
 Hypoxia dependent
 Hypoxia independent
 Epo independent
 Apparent / Relative
 Reduction in plasma volume

35. POLYCYTHEMIA VERA
 Chronic, clonal myeloproliferative disorder
characterized by an absolute increase in number
of RBCs
 2-3 / 100000
 Median age at presentation: 55-60
 M/F: 0.8:1.2

36. POLYCYTHEMIA VERA
JAK2 Mutation
 JAK/STAT: cellular proliferation and cell
survival
 deficiency in mice at embryonic stage is lethal due
to the absence of definitive erythropoiesis
 Abnormal signaling in PV through JAK2 was
first proposed in 2004
 a single nucleotide JAK2 somatic mutation
(JAK2V617F mutation) in the majority of PV
patients

37. Polycythaemia vera
(Polycythaemia rubra vera)
 Definition of polycythemia
 Raised packed cell volume (PCV / HCT)
 Male > 0.51 (50%)
 Female > 0.48 (48%)
 Classification
 Absolute
 Primary proliferative polycythaemia (polycythaemia
vera)
 Secondary polycythaemia
 Idiopathic erythrocytosis
 Apparent
 Plasma volume or red cell mass changes

38. Polycythaemia vera
(Polycythaemia rubra vera)
 Polycythaemia vera is a clonal stem cell disorder
characterised by increased red cell production
 Abnormal clones behave autonomous
 Same abnormal stem cell give rise to granulocytes and
platelets
 Disease phase
 Proliferative phase
 “Spent” post-polycythaemic phase
 Rarely transformed into acute leukemia

39. Polycythaemia vera
(Polycythaemia rubra vera)
 Clinical features
 Age
 55-60 years
 May occur in young adults and rare in childhood
 Majority patients present due to vascular
complications
 Thrombosis (including portal and splenic vein)
 DVT
 Hypertension
 Headache, poor vision and dizziness
 Skin complications (pruritus, erythromelalgia)
 Haemorrhage (GIT) due to platelet defect

40. Polycythaemia vera
(Polycythaemia rubra vera)
 Hepatosplenomegaly
 Erythromelalgia
 Increased skin temp
 Burning sensation
 Redness
Liver
40%
Spleen
70%
Erythromelalgia

41. Polycythaemia vera
(Polycythaemia rubra vera)
 Laboratory features and
morphology
 Hb, PCV (HCT), and Red
cell mass increased
 Increased neutrophils
and platelets
 Normal NAP
 Plasma urate high
 Circulation erythroid
precursors
 Hypercellular bone
marrow
 Low serum
erythropoietin
Bone marrow in PV

42. Polycythaemia vera
(Polycythaemia rubra vera)
 Treatment
 To decrease PVC (HCT)
 Venesection
 Chemotherapy
 Treatment of complications

43. Clinical features
 Plethora
 Persistent leukocytosis
 Persistent thrombocytosis
 Microcytosis secondary to iron deficiency
 Splenomegaly
 Generalized pruritus (after bathing)
 Unusual thrombosis (e.g., Budd-Chiari syndrome)
 Erythromelalgia (acral dysesthesia and erythema)

44. Clinical features
 Hypertention
 Gout
 Leukaemic transformation
 Myelofibrosis

45. Diagnostic Criteria
A1 Raised red cell mass
A2 Normal O2 sats and EPO
A3 Palpable spleen
A4 No BCR-ABL fusion
B1 Thrombocytosis >400 x 109/L
B2 Neutrophilia >10 x 109/L
B3 Radiological splenomegaly
B4 Endogenous erythroid colonies
A1+A2+either another A or two B establishes PV

47. Treatment
 The mainstay of therapy in PV remains phlebotomy to keep the
hematocrit below 45 percent in men and 42 percent in women
 Additional hydroxyurea in high-risk pts for thrombosis (age over
70, prior thrombosis, platelet count >1,500,000/microL, presence of
cardiovascular risk factors)
 Aspirin (75-100 mg/d) if no CI
 IFNa (3mu three times per week) in patients with refractory
pruritus, pregnancy
 Anagrelide (0.5 mg qds/d) is used mainly to manage
thrombocytosis in patients refractory to other treatments.
 Allopurinol

48. Causes of secondary polycythemia
 ERYTHROPOIETIN (EPO)-MEDIATED
 Hypoxia-Driven
 Chronic lung disease
 Right-to-left cardiopulmonary vascular shunts
 High-altitude habitat
 Chronic carbon monoxide exposure (e.g., smoking)
 Hypoventilation syndromes including sleep apnea
 Renal artery stenosis or an equivalent renal pathology
 Hypoxia-Independent (Pathologic EPO Production)
 Malignant tumors
 Hepatocellular carcinoma
 Renal cell cancer
 Cerebellar hemangioblastoma
 Nonmalignant conditions
 Uterine leiomyomas
 Renal cysts
 Postrenal transplantation
 Adrenal tumors

49. Causes of secondary polycythemia
 EPO RECEPTOR–MEDIATED
 Activating mutation of the erythropoietin
receptor
 DRUG-ASSOCIATED
 EPO Doping
 Treatment with Androgen Preparations

50. Secondary polycythaemia
 Polycythaemia due to known causes
 Compensatory increased in EPO
 High altitude
 Hulmonary diseases
 Heart dzs eg- cyanotic heart disease
 Abnormal hemoglobin- High affinity Hb
 Heavy cigarette smoker
 Inappropriate EPO production
 Renal disease-carcinoma, hydronephrosis
 Tumors-fibromyoma and liver carcinoma

51. Secondary polycythaemia
 Arterial blood gas
 Hb electrophoresis
 Oxygen dissociation curve
 EPO level
 Ultrasound abdomen
 Chest X ray
 Total red cell volume(51Cr)
 Total plasma volume(125 I-
albumin)

52. Relative polycythaemia
 Apparent polycythaemia or
pseudopolycythaemia due to
plasma volume contraction
 Causes
 Stress
 Cigarette smoker or alcohol intake
 Dehydration
 Plasma loss- burn injury

53. Differentiation of PV, Secondary
PV and Relative Erythrocytosis
Features PV 2ndary
PV
Rel.
Erythro
organo-
megaly
present absent absent
O2 Sat Normal Dec. Normal
RBC mass Inc Inc Normal
EPO Dec Inc Normal
WBC Inc Normal Normal

54. Essential Thrombocytosis
 Clonal stem cell disorder
characterized by marked
thrombocytosis and abnormal
platelet function
 Plt count 600-2500 X 109/L
 Abnormal plt aggregation studies

55. Essential Thrombocythaemia (ET)
 Clonal MPD
 Persistent elevation of Plt>600 x109/l
 Poorly understood
 Lack of positive diagnostic criteria
 2.5 cases/100000
 M:F 2:1
 Median age at diagnosis: 60, however 20% cases <40yrs

56. Clinical Features
 Vasomotor
 Headache
 Lightheadedness
 Syncope
 Erythromelalgia (burning pain of the hands or
feet associated with erythema and warmth)
 Transient visual disturbances (eg, amaurosis
fujax, scintillating scotomata, ocular migraine)
 Thrombosis and Haemorrhage
 Transformation

57. Investigations
ET is a diagnosis of exclusion
 Rule out other causes of elevated platelet count

58. Diagnostic criteria for ET
 Platelet count >600 x 109/L for at least 2 months
 Megakaryocytic hyperplasia on bone marrow
aspiration and biopsy
 No cause for reactive thrombocytosis
 Absence of the Philadelphia chromosome
 Normal red blood cell (RBC) mass or a HCT <0.48
 Presence of stainable iron in a bone marrow
aspiration
 No evidence of myelofibrosis
 No evidence of MDS

62. Therapy of ET based on the risk of thrombosis

63. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
 Clonal myeloproliferative disease of
megakaryocytic lineage
 Sustained thrombocytosis
 Increase megakaeryocytes
 Thrombotic or/and haemorrhage episodes
 Positive criteria
 Platelet count >600 x 109/L
 Bone marrow biopsy; large and increased megas.

64. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
 Criteria of exclusion
 No evidence of Polycythaemia vera
 No evidence of CML
 No evidence of myelofibrosis (CIMF)
 No evidence of myelodysplastic syndrome
 No evidence of reactive thrombocytosis
 Bleeding
 Trauma
 Post operation
 Chronic iron def
 Malignancy
 Chronic infection
 Connective tissue disorders
 Post splenectomy

65. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
 Clinical features
 Haemorrhage
 Microvascular occlusion
 TIA, gangrene
 Splenic or hepatic vein
thrombosis
 Hepatosplenomegaly

66. Essential thrombocythaemia
Primary thrombocytosis / idiopathic thrombocytosis
 Treatment
 Anticoagulant
 Chemotherapy
 Role of aspirin
 Disease course and prognosis
 25 % develops myelofibrosis
 Acute leukemia transformation
 Death due to cardiovascular complication

67. Agnogenic Myeloid Metaplasia
 Stem cell mutation causes
hematopoietic abnormalities
 Extramedullary hematopoiesis
 BM fibrosis:uncontrolled production of
fibroblasts from degenerating platelets result
in dense thread-like scar tissue: dry BM tap
 Differences from CML
 LAP inc., Ph neg, nRBC, splenomegaly, tear
drop cell

68. Myelofibrosis

69. Myelofibrosis
 Myeloproliferative disorder (monoclonal stem cell
disorder) in which increased marrow fibrosis is
dominant feature
 Rare
 50-70 yrs
 Clinical: fatigue, weakness, malaise, fever/night
sweats, abdominal pain, anorexia/wt loss,
nasuea/vomiting
 May be primary or secondary (breast cancer,
prostate cancer, Hodgkin's disease, non-Hodgkin's
lymphoma, autoimmune diseases)
 Hematopoietic stem cells grow out of control,
producing both immature blood cells and excess
fibrous tissue—replacing normal marrow

70. Myelofibrosis
 Extramedullary hematopoeisis—hepatic and
splenic enlargement, thoracic paravertebral
masses
 Bones
 Uniform or heterogeneous increased density
 Spine (“sandwich sign” or diffuse density),
pelvis, skull, ribs, proximal femur/humerus
 Cortical thickening in long bones
 Decreased T1 and T2 marrow signal
 Bone marrow bx needed to confirm dz
 Progressive bone marrow failure = severe anemia
/ thrombocytopenia/leukopenia
 risk of bleeding/infection
 Slowly progressive dz leading to death
 No available tx to effectively reverse progression;
possible cure with bone marrow or stem cell
transplantation (significant risks)

71. Myelofibrosis
Chronic idiopathic myelofibrosis
 Progressive fibrosis of the marrow & increase
connective tissue element
 Agnogenic myeloid metaplasia
 Extramedullary erythropoiesis
 Spleen
 Liver
 Abnormal megakaryocytes
 Platelet derived growth factor (PDGF)
 Platelet factor 4 (PF-4)

72. Myelofibrosis
Chronic idiopathic myelofibrosis
 Insidious onset in older
people
 Splenomegaly- massive
 Hypermetabolic symptoms
 Loss of weight, fever and
night sweats Myelofibrosis
Chronic idiopathic myelofibrosisc
 Bleeding problems
 Bone pain
 Gout
 Can transform to acute
leukaemia in 10-20% of
cases

73. Myelofibrosis
Chronic idiopathic myelofibrosis
 Anaemia
 High WBC at presentation
 Later leucopenia and
thrombocytopenia
 Leucoerythroblastic blood
film
 Tear drops red cells
 Bone marrow aspiration-
Failed due to fibrosis
 Trephine biopsy- fibrotic
hypercellular marrow
 Increase in NAP score