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MYELOPROLIFERATIVE DISEASES
By
DR. FATIMA AL-QAHTANI
CONSULTANT HAEMATOLOGIST
WHO Classification Chronic Myeloproliferative Disease
---------------------------------------------------------------------------------------------------------------------------
• Chronic Myelogenous Leukaemia [Ph chromosome, t(9;22)(q34;q11), BCR/ABL- positive ]
• Chronic Neutrophilic Leukaemia• Chronic Eosinophilic Leukaemia
(and the hypereosinophilic syndrome)• Polycythaemia Vera• Chronic Idiopathic Myelofibrosis
(with extramedullary haematopoiesis)• Essential Thrombocythaemia
• Chronic Myeloproliferative Disease, Unclassifiable
WHO Classification Myelodysplastic / Myeloproliferative Diseases
-----------------------------------------------------------------
• Chronic Myelomonocytic Leukaemia
• Atypical Chronic Myeloid Leukaemia
• Juvenile Myelomonocytic Leukaemia
• Myelodysplastic/Myeloproliferative Disease, Unclassifiable
Myeloid Disorders Usual Features at Diagnosis
DiseaseBM
cellularity
% Marrow Blasts
Maturation Morphology Haemato-poiesis
Blood count (s)
Organo-megaly
Myeloproliferatie disorder
Usually increased
Normal or slightly increased (<10%)
Present Relatively normal
Effective One or more myeloid cell lines increased
Common
Myelodysplastic syndromes
Usually increased, occasionally decreased
Normal or increased (<20%)
Present Dysplasia of one or more myeloid lineage
Ineffective Cytopenia (S) Uncommon
Myelodysplastic/ myeloproliferative disease
Usually increased
Normal or increased (<20%)
Present Dysplasia of one or more myeloid lineages frequent
Effective or ineffective; may vary among involved lineages
Variable Common
Acute myeloid leukaemia
Usually increased, occasionally decreased
Increased
(≥ 20%)
Varies, frequently minimal
May or may not be associated with dysplasia in one or more myeloid lines
Ineffective or effective
Variable uncommon
Myeloproliferative Disease
Recurring Genetic Abnormalities and Their Frequency (%)
at diagnosisDisease Specific abnormalities (%) Recurring, nonspecific
cytogenetic/genetic abnormalities(%)
CML, CP t(9;22)(q34;q11), BCR/ABL 100
CML, AP/BP
t(9;22)(q34;q11), BCR/ABL 100 +8, +9Ph,+19,i(17q), t(3;21)(q26;q22)(EVI1/AML1) 80
CNL None +8, +9, del(20q), del(11q14) ~10
CEL None +8, t(5;12)(q33;p13)(TEL/PDGFβR), dic(1;7), 8p11 (FGFR1)
?
PV None +8, +9, del(20q), del(13q), del(1p11) ~15
CIMF None +8, del(20q), -7/del(7q), del(11q), del(13q) ~35
ET None +8, del (13q) ~5
CML, CP = Chronic myelogenous leukaemia, chronic phase; CML, AP/BP= Chronic myelogenous leukaemia, accelerated or blast phase;
CNL = Chronic neutrophilic leukaemia; CEL = Chronic eosinophilic leukaemia; PV = Polycythaemia Vera;
EVI-1 = ecotropic viral integration site 1 CIMF = Chronic idiopathic myelofibrosis; ET = Essential thrombocythaemia ? = Insufficient data available
Chronic Idiopathic Myelofibrosis Prefibrotic Stage
Clinical findings Morphological findingsSpleen and liver:
No or mild splenomegaly or hepatomegaly
Blood:
• No or mild leukoerythroblastosis
• No or minimal red blood cell
poikilocytosis; few if any dacrocytes
Splenomegaly:
Haematologic parameters variable, but often:
• Mild anaemia
• Mild to moderate leukocytosis
• Mild to marked thrombocytosis
Bone marrow:
Hypercellularity
Neutrophilic proliferation
Megakaryocytic proliferation and
atypia (Clustering of megakaryocytes,
abnormally lobulated megakaryocytic
nuclei, naked megakaryocytic nuclei)
Minimal or absent reticulin fibrosis
Chronic Idiopathic Myelofibrosis Fibrotic Stage
Clinical findings Morphological findingsSpleen and liver:
Moderate to marked splenomegaly and hepatomegaly
Blood:
Leukoerythroblastosis
Prominent red blood cell
poikilocytosis with dacrocytes
Haematology:
• Moderate to marked anaemia
• Low, normal or elevated WBC
• Platelet count decreased, normal
or elevated
Bone Marrow:
Reticulin and/or collagen fibrosis
Decreased cellularity
Dilated marrow sinuses with
intraluminal haematopoiesis
Prominent megakaryocytic
proliferation and atypia (clustering
of megakaryocytes, abnormally
lobulated megakaryocytic nuclei,
naked nuclei)
New bone formation (osteosclerosis)
Essential ThrombocythaemiaDiagnostic Criteria
Positive Criteria1. Sustained platelet count ≥600X109/L
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes
Criteria of exclusion1. No evidence of polycythaemia vera (PV)
- Normal red cell mass or Hb <18.5g/dl in men, 16.5g/dl in 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 Hgb levels to the PV range
2. No evidence of CML
- No Philadelphia chromosome and no BCR/ABL fusion gene
Essential Thrombocythaemia Diagnostic criteria (Continued)
3. No evidence of chronic idiopathic myelofibrosis- Collagen fibrosis absent
- Reticulin fibrosis minimal or absent
4. No evidence of myelodysplastic syndrome- No del(5q), t(3;3)q21;q26), inv(3)(q21q26)
- No significant granulocytic dysplasia, few if any
micromegakaryocytes
5. No evidence that thrombocytosis is reactive due to:- Underlying inflammation or infection
- Underlying neoplasm
- Prior splenectomy
Giant Plat
Megakaryocytes in Clusters
Polycythaemia Vera
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
- Hb : >17.5 gm/dl > 15.5 gm/dl
- RBC : > 6.0 X 1012/L
> 5.5X1012/L
- PCV : > 51%
> 48%
- TRCV : > 36 ml/kg (25-35)
> 32 ml/kg (22-32)
- TPV : 40 – 50 ml/kg
Classification of Erythrocytosis
Raised PCV (female >0.48; male>0.51)
RCM
(Interpreted using ICSH reference values)
Increased RCM Normal RCMAbsolute erythrocytosis Apparent erythrocytosis
Abbreviations: PCV = Packed Cell Volume; RCM = red cell mass;
ICSH = International Council for Standardization in Haematology;
Primary ErythrocytosisCongenital #
Truncation of the EPO receptor*
Acquired
Polycythaemia Vera*
Secondary ErythrocytosisCongenital #
e.g., high oxygen affinity Hb,
autonomous high EPO production
Acquired
e.g., hypoxemia, renal disease
# Sometimes familial
* The only condition to be defined in this category at present
EPO = erythropoietin
Polycythaemia VeraCauses
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
• Primary : Polycythaemia Vera• Secondary:
1. Erythropoietin compensatory increase:
High Altitude
C.V. disease
Pulmonary disease
High Affinity Hb
Heavy smoking
Methaemoglobinaemia
2. Abnormal erythropoietin production:
Renal diseases.
Massive uterine fibromatosis
Hepatocellular Carcinoma
Cerebellar Haemangioblastoma• Relative: Stress, Dehydration, Plasma Loss.
Polycythaemia VeraClinical Features
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
• Headache, Lethargy, Dyspnea• Weight Loss, Night Sweats• Generalized pruritis (Increase after hot bath)• Plethoric Appearance• Haemorrhage & Thrombosis• Hypertension (In about 1/3rd of the patients)• Gout (Increased Uric Acid)• Peptic Ulcers (In 5 – 10% of the patients)• Splenomegaly (In 2/3rd of patients)• Accidental Discovery (On Routine exam)
Polycythaemia VeraLaboratory Investigations
----------------------------------------------------------------------------------------------------------------------------------------------------------------------
- C.B.C
- Neutrophil Alkaline Phosphatase (N.A.P.)
- Serum B12 & B12 binding capacity
- Bone Marrow - Blood Viscosity
- Uric Acid Level - Hb Electrophoresis
- Arterial Oxygen Tension - T.R.C.V.- I.V. Pyelography, CT & US - JAK2: 74 – 97 % (PV)
- Erythropoietin Assay 33 – 57 % (ET)
35 – 50 % (MF)
Polycythaemia Vera Proposed diagnostic criteria
-------------------------------------------------------------------------------------------------------------------------------
A1 Raised red cell mass B1 Thrombocytosis
(>25% above mean normal Platelet count>400X109/1
predicted value)
A2 Absence of a cause of B2 Neutrophil leukocytosis
Secondary Polycythaemia neutrophil count >10X109/1
A3 Palpable splenomegaly B3 Splenomegaly demonstrated
by isotope/ultrasound scanning
A4 Clonality marker B4 Characteristic BFU-E growth
e.g., abnormal marrow karyotype or reduced serum erythropoietin------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A1 + A2 + A3 or A4 establishes PV
A1 + A2 + Two of B establishes PV
Polycythaemia Vera Classic Polycythaemia Vera Study Group
Diagnostic Criteria --------------------------------------------------------------------------------------------------------------------------------------------------------------------------
A1 ↑ Red Cell Mass B1 Thrombocytosis
Male ≥36 ml/kg Platelet count >400,000/µl
Female ≥32ml/kg B2 Leukocytosis >12,000/µl
(No fever or infection)
A2 Normal Arterial B3 ↑ Leukocyte Alkaline
O2 Saturation ≥92% Phosphatase score >100
(No fever or infection)
A3 Splenomegaly ↑ Serum B12 (>900pg/ml)
or
↑ Unbound B12 binding
capacity (>2200pg/ml)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------
• Diagnosis is acceptable if the following combinations are present: A1 + A2 + A3 or A1 + A2 + any two from Category B.
Polycythaemia Vera
Treatment -------------------------------------------------------------
-
• Venesecton
• Radioactive Phosphorus (P32)
• Chemotherapy: e.g. Hydroxyurea
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